REVIEW ARTICLE

X-linked diseases: susceptible females

Barbara R. Migeon, MD 1

The role of X-inactivation is often ignored as a prime cause of sex data include reasons why women are often protected from the differences in disease. Yet, the way males and females express their deleterious variants carried on their X chromosome, and the factors X-linked genes has a major role in the dissimilar phenotypes that that render women susceptible in some instances. underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the Genetics in Medicine (2020) 22:1156–1174; https://doi.org/10.1038/s41436- heart, blood, skin, muscle, and bones. Summarized here are many 020-0779-4 examples of the different presentations in males and females. Other

INTRODUCTION SEX DIFFERENCES ARE DUE TO X-INACTIVATION Sex differences in human disease are usually attributed to The sex differences in the effect of X-linked pathologic variants sex specific life experiences, and sex hormones that is due to our method of X chromosome dosage compensation, influence the function of susceptible genes throughout the called X-inactivation;9 humans and most placental mammals – genome.1 5 Such factors do account for some dissimilarities. compensate for the sex difference in number of X chromosomes However, a major cause of sex-determined expression of (that is, XX females versus XY males) by transcribing only one disease has to do with differences in how males and females of the two female X chromosomes. X-inactivation silences all X transcribe their gene-rich human X chromosomes, which is chromosomes but one; therefore, both males and females have a often underappreciated as a cause of sex differences in single active X.10,11 disease.6 Males are the usual ones affected by X-linked For 46 XY males, that X is the only one they have; it always pathogenic variants.6 Females are biologically superior; a comes from their mother, as fathers contribute their Y female usually has no disease, or much less severe disease chromosome. However, because X chromosomes are silenced than the male with the same variant, unless she is in a random fashion, females usually have two kinds of cells in homozygousforthedeleteriousallele,oritislethalfor every tissue; those with their maternal X active and those with males. an active paternal X. Females are protected to a large extent The X chromosome carries 867 known protein coding because their two X chromosomes most often differ in genetic genes.7 Clearly, pathogenic variants that induce complete loss content. of function may be lethal to fetuses of both sexes; however, a Sex differences in diseases due to deleterious variants number of these pathogenic variants—less severe, or occur- encoded by the X chromosome originate from the sex ring in less-essential genes—cause at least 533 X-linked difference in the expression of the variant allele; if present diseases8 that affect males more severely.8 Rather in male tissues, it is expressed in every cell, but if present in than influencing sexual development, most of these genes female tissues, the variant is usually expressed in only half the play a role in nonreproductive human tissues, including cells (Fig. 1). brain, bone, blood, ears, heart, liver, kidney, retina, skin, and teeth. FEMALES ARE MOSAICS Table 1 provides data about a substantial number of X- A woman is less susceptible to the pathogenic variants in linked disorders obtained in large part from OMIM8 that genes on her active X chromosome because the variant is not confirm the lesser susceptibility of females. The table is not expressed in all her cells.12 all-inclusive, but it provides enough data to show the greater severity of these diseases in males, and to illustrate why FEMALES CAN AMELIORATE THE EFFECTS OF some,butnotall,femaleswiththesameX-linked PATHOGENIC VARIANTS deleterious allele are protected from its effects. This paper Most women do not manifest X-linked disorders because (1) is motivated by the question: When so many women are they are not homozygous for the pathogenic variant, and (2) protected from manifesting severe X-linked diseases, why their variant cells (those expressing the deleterious allele) are some of them susceptible? receive sufficient gene product to carry out the essential

1Departments of Genetic Medicine and Pediatrics, The Johns Hopkins Medical Institutions, Baltimore, MD, USA. Correspondence: Barbara R. Migeon ([email protected]) Submitted 24 September 2019; accepted: 5 March 2020 Published online: 14 April 2020

1156 Volume 22 | Number 7 | July 2020 | GENETICS in MEDICINE 1234567890():,; EEISi MEDICINE in GENETICS MIGEON Table. 1 Effect of X-inactivation (XI) on phenotype and cell selection in X-linked disorders. X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Aarskog–Scott syndrome Xp11.2 FGD1 305400 Faciogenital dysplasia Subtle features as widows ND allelic with XLMR 16 54,445,453 premature termination; (ocular hypertelorism, peak or short stature truncation shawl scrotum) with Skewing toward mutant attention deficit increases severity (i.e., hyperactivity, also XLID translocation) | FGD1 oue22 Volume XLMR 16 Xp11.22 305400 ID only No affected females ND 54,445,453 missense Acrogigantism X-LAG Xq26.3 CD40LG 300942 Microduplications: only Females are like mosaic Microduplications have Lymphocytes AR allelic with X-linked 136,648,176 300386 mosaic males are cited, so males; acrogiantism, but no random XI immunodeficiency with microduplication may be lethal in most immunodeficiency Affected females may not | ubr7 Number hyper IGM males; mosaic males have Elevated growth hormone & be skewed until older age acrogigantism, but no prolactin immunodeficiency Immunodeficiency with Xq26.3 CD40LG (CD40 ligand on 308230 Decreased IgG, IgA, & IgE; Heterozygotes have normal Not convincing as reports T and B cells &

| hyper IGM (HIGM) 136,648,176 T cells) susceptibility to levels of IgG, IgA, IgM, & IgE conflict; it seems that half fibroblasts uy2020 July Immunodeficiency 3 variants opportunistic bacterial normal is enough to protect diseases, leading to liver females disease; most have severe infections & shortened life spans Adrenoleukodystrophy Xq28 ABCD1 300100 Demyelinization of brain, Adrenomyeloneuropathy; Yes, gradual. Favors WBC, RBC, skin G6PD & 153,724,850 spinal cord, & adrenals. spastic paraplegia with age mutant allele fibroblasts clones fatty acids Often death in first decade Alport syndrome Xq22.3 COL4A5 301050 End stage renal disease; Milder renal disease Severity related to skewing WBC HPRT & PGK. 108,439,837 hearing loss; ocular Severity related to skewing toward mutant allele Kidney glomeruli COL45A malformations Immunolabel Amelogenesis imperfecta Xp22.2 AMELX 301200 Hypoplastic amelogenesis Vertically grooved teeth; One homozygous female WBC AR 11,293,412 imperfecta; variable depending on was affected like her Mottled teeth (fluoride skew of XI hemizygous father, and independent); more severe than her Homogeneous pattern of heterozygous mother; abnormality mother 25% skewed AMELY expressed at 10% toward mutant, reflected in activity of AMELX degree of grooving Androgen insensitivity Xq12 AR 300068 Feminization or No affected females ND Skin fibroblast Androgen 67,544,020 loss of function hypospadias and Not severe (two clonal clones, both binding hypomorphic micropenis populations, but lower normal and binding in heterozygotes) mutant present Kennedy spinal bulbar & Xq12 AR 313200 36–62 repeats in males; Affected, if homozygous, but ND muscular atrophy 67,544,020 trinucleotide repeat onset: 3rd–5th decade; less affected because of expansion slowly progressive muscle higher androgens in males; atrophy; progressive heterozygotes usually decrease in sperm normal, but some production muscle cramps ATRX syndrome Xq21.1 ATRX 301040 ID, thalassemia, Hemoglobin H inclusions Yes, severe toward wild WBC, AR ɑ-thalessemia/ID syndrome 77,504,877 300032 genital abnormalities Mild retardation, usually type allele buccal smear attributable to variants in unaffected PHD domain ARTICLE REVIEW ɑ-thalessemia Xq21.1 ATRX 300448 Severe variant reducing No affected females Yes, severe toward wild WBC AR Myelodysplastic syndrome 77,504,877 activity to 3–4% normal type allele MR-hypotonic facies Xq21.1 ATRX 309580 Not so severe variants or No affected females Yes, severe toward wild WBC AR syndrome 77,504,877 those in the helical domain type allele No genital abnormalities Barth syndrome Xq28 TAZ 302060 Idiopathic cardiomyopathy No affected females Yes, severe toward wild WBC, fibroblasts AR in obligate 154,411,517 Methylglutaconic type allele heterozygotes aciduria Abnormal mitochondria Death in childhood Borjeson–Forssman–Lehmann Xq26.2-3 PHF6 301900 ID, obesity, Mild ID Yes, severe toward wild WBC FMR1, AR PGK1 syndrome 134,373,311 hypogonadism, epilepsy, 11 females with de novo type allele 1157 facial dysmorphism variants have Coffin–Siris If unskewed, then phenotype all skewed 100% manifesting at least a little 1158 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay toward mutant allele, female If skewed severely toward with 70% skewing had mutant, then severe disease milder symptoms Bruton agammaglobulinemia Xq22.1 BTK 300300 B-cell deficiency; boys lack No affected females Yes, severe >95% B cells AR 101,349,446 circulating B cells; they are overcome by bacterial infections Cataract 40 Xp22.1-22.2 NHS 302200 Congenital cataracts with Normal vision but develop ND Allelic with Nance–Horan 17, 375,199 Lack of NHS leads to NH severe visual impairment & cataracts in their 40s syndrome syndrome; milder microcornea variants give cataracts Associated with triplication of the locus Nance–Horan Syndrome Xp22 NHS 302350 Congenital cataract Slightly reduced vision ND 17, 375,199 leading to profound vision loss; dysmorphic features and malformed teeth Microcornea, microphthalmia, and mild or moderate ID Charcot–Marie–Tooth Xq13.1 GJB1 302800 Sensory & peripheral Milder No WBC AR CMTX1 71,215,211 304040 neuropathies Charcot–Marie–Tooth Xq22.3 PRPS1 311070 Optic atrophy, Milder No skewing determines WBC AR CMTX5 107,628,423 polyneuropathy, & severity Allelic with DFNX1 deafness & PRPS1 related gout Charcot–Marie–Tooth Xp22.11 PDK3 300905 1 three-generation family Subtle features such as hand ND CMTX6 24,465,226 Males more severe than tremor with age females Foot deformities, abnormal gait muscle weakness, sensory abnormalities Christianson syndrome Xq26.3 SLC9A6 (NHE6) 300231 Profound ID; mute; Milder ND 135,974,595 developmental regression; Psychiatric disorders impaired ocular Study of 20 female movements heterozygotes shows deficit Epilepsy; microcephaly; in at least one neurocognitive cerebellar and brain stem domain (ID 20%, learning oue22 Volume atrophy differences 31%, speech delays 30%, & ADHD 20%); atypical parkinsonism, with age NSDHL NSDHL | CHILD syndrome Xq28 308050 Fetal lethal Hemidysplasia with Unilateral Yes, (in mice) Brain, skin, liver activity ubr7 Number 152 830, loss of function ichthyosis of Bare 966 missense & nonsense Patches mice CK syndrome Xq28 NSDHL 300831 ID plus neonatal seizures Heterozygotes not affected ND Analogous to bare patches in 152 830, 300275 Only males affected; |

uy2020 July mice 966 hypomorphic variant Defect in cholesterol Allelic with CHILD syndrome synthesis Chondrodysplasia punctata 1 Xp22.23 ARSE 302950 ID, bone defects; Milder symptoms No WBC & fetal AR 2,934,631 sometime small short stature; Mild cases not affected tissues

| chromosomal deletions epiphyseal stippling EEISi MEDICINE in GENETICS Chondrodysplasia punctata 2 Xp11.23 EPB 302960 Fetal lethal; Bilateral ichthyosis No WBC AR (Conradi–Hunermann 48,521,807 Emopamil binding Facial skin and skeletal Short stature syndrome) CDPX2 protein dysplasia Epiphyseal stippling Allelic with Mend syndrome Only mosaic males survive Hair and skin defects Occasionally severe due to skewed XI Conradi–Hunermann–Happle Xp11.23 EBP 302960 Mosaic grandfather (50%) Mother: short stature; Random XI in blood of both WBC AR splicing syndrome CDPX2 48,521,807 Short stature Mosaic skin defect fetus & mother (not shown) pathogenic MIGEON Fetus: severe bone Perhaps skewed in affected variant in EBP abnormalities; no skin rash tissues EEISi MEDICINE in GENETICS MIGEON Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay causing extreme familial variability MEND syndrome Xp11.23 EBP 300960 Nonmosaic; ID; short, Heterozygotes are usually ND 48,521,807 Hypomorphic variant scoliosis; abnormal digits; unaffected missense cataracts and dermatitis | oue22 Volume Congenital disorder of Xp11.23 SLC35A2 300896 All affected males are Females are affected with Affected females with WBC AR glycosylation CDG2M 48,903,182 UDP galactose transporter mosaics infantile epileptic truncating variants are Loss of function encephalopathy highly skewed toward wild type; one female with de

| novo splice site variant had ubr7 Number random XI Chronic granulomatous Xp21.1-11.4 CYBB 306400 Severe bacterial infections Discoid lupus No WBC, buccal AR disease 37,780, 016 Cytochrome B Beta Rare, severely affected female subunit due to skewing | uy2020 July CGD (large study of 93 Xp21.1-11.4 CYBB 306400 Not applicable Milder symptoms associated Severe carriers had low DHR WBC %DHR+ females only) 37,780, 016 with higher Sisters & twins highly dehydrorhodamine oxidation correlated, but not with (DHR); low DHR associated mothers with manifestations No progressive skewing over time Immunodeficiency 34 Xp21.1-11.4 CYBB 300645 Severe mycobacterial Rare female ND 37,780, 016 missense & nonsense infections (some TB) variant Coffin–Lowry Xp22.12 RPS6KA3 303600 ID; short stature; abnormal Milder ID than male Yes, all seem to have WBC AR RSK2 Allelic to XLMR 19 20,149,910 (RSK2) facies, gait, & fingers; significant skewing; Small deletions & small microcephaly direction not clear save for 2 duplication mothers with predominant Missense variants wild type cells X-linked mental retardation Xp22.12 RPS6KA3 300854 Moderate ID with no other Milder nonsyndromic ID ND 19 20,149,910 (RSK2) anomalies Hypomorphic Coagulation factor 8 Xq28 F8 306700 Severe <1%, moderate Most heterozygotes have No, but skewing causes WBC AR 154,835,787 2–6% or mild 6–30% 50% so are clinically normal; manifestations. residual activity affected if homozygous Familial skewing in mutants or if XI skewed manifesting heterozygotes Coagulation factor 9 Xq27.1 F9 300746 Affected are mainly males Affected females usually have No, but severe skewing WBC AR 139,530,719 skewed X-inactivation or are responsible for manifesting homozygous heterozygotes Cornelia de Lange syndrome Xp11.22 SMC1A 300590 More severe and Most of the affected are Escape gene 5% cases attributed to 53,374,148 Missense fetal lethal females ND SMC1A ID, facial dysmorphisms, ID, poor growth, (Cornelia de Lange, 2) seizures, limb microcephaly, dysgenesis of abnormalities corpus callosum Cornelia de Lange, 2 Xp11.22 SMC1A 300040 Fetal lethal Infantile epilepsy ND 53,374,148 Truncating variants HDAC8 AR Cornelia de Lange Xq13.2 300882 Facial dysmorphism; Milder Extreme, with mutant allele WBC ARTICLE REVIEW 5 72,329,515 ID; multiple congenital inactive Allelic with XLMR abnormalities Wilson–Turner XLMR Wilson–Turner Xq13.2 HDAC8 300269 ID, microcephaly Milder Yes, extreme WBC Allelic with Cornelia de Lange 72,329,515 Point variants Craniofacial deformities 5 Craniofrontonasal syndrome Xq13.1 EFNB1 304110 Hypertelorism Craniosynostosis; craniofacial No, variant produces Blood, AR 68,828,996 Heterozygous loss of asymmetry; hypertelorism; cellular interference cranioperiosteum immunochemistry function frontonasal dysplasia; skeletal abnormalities Creatine transporter defect Xq28 SLC6A8 300352 ID, speech delay, seizures Milder No Skin fibroblasts, AR 153,687,925 blood, hair roots LAMP2 AR 1159 Danon disease Xq24 300257 ID, cardiomyopathy, Later onset Discordant identical twins; IPS T cells 120,426,147 skeletal muscle weakness complete skew for affected 1160 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Skew responsible for heterozygous phenotype Deafness X-linked 1 Xq22.3 PRPS1 304500 Phenotypic spectrum with Females have mild high pitch ND Allelic with 107,628,423 Charcot–Marie–Tooth hearing loss Charcot–Marie–Tooth 5 Males more severe than females Deafness, X-linked 4 Xp22.12 SMPX 300066 Nonsyndromic postlingual Onset 3–48 years XI skewing influences WBC AR 21,705,971 hearing loss (mean 28.8) phenotype Earlier onset in males 2–10 years (mean 3.3 years) Dent disease1 Xp11.23 CLCN5 300009 Nephrolithiasis Less severe; First cases show 1/1 and 2/4 WBC & urine AR and deep 49,922,595 Proteinuria rare hypercalciuria; cases of extreme skewing sediment sequencing Hypophosphotemic rickets almost never chronic renal toward mutant in affected disease females Dent disease 2 Xq26.1 OCRL1 300535 Proteinuria; Heterozygotes not affected ND 129,540,258 Mild variant of Lowe Hypercalcemia; syndrome Nephrocalcinosis. No renal tubular acidosis, Dent disease 2 Digenic Xp11.23, CLCN5, OCRL1 300009 Abnormal facies, ocular Heterozygotes not affected Yes, severe WBC mRNA 49,922,595 (digenic) 300535 abnormalities, rickets, Xq26.1 delayed growth 129,540,258 Diabetes insipidus (nephrogenic) Xq28 AVPR2 304800 90% are X-linked (10% Heterozygotes not affected Asymptomatic WBC AR 159,902,624 are autosomal); inability to heterozygotes have concentrate urine; random XI unresponsive to (4 heterozygotes normal antidiuretic hormone with 50–60% XI) Skewing toward mutant leads to disease Dyskeratosis congenita Xq28 DKC1 305000 Defective telomeres; None or milder Yes, extreme WBC, buccal AR 154,762,741 premature aging; multiple tissues bone marrow failure Dystonia parkinsonism (XDP) Xq13.1 TAF1 314250 Adult onset dystonia and Most heterozygotes not ND Filipino type 71,366,219 Retrotransposon insert symptoms of Parkinson affected; a few affected have disease mild dystonia, later onset manifestors said to have XI skewed toward mutant, but no oue22 Volume studies documented XLID 33 Xq13.1 TAF1 300966 12 boys (9 families); global Heterozygotes not affected Yes, 100% skewing toward WBC AR & RP2 (only 71,366,219 Missense variants delay; syndromic ID normal allele WT allele in RNA hypotonia; facial confirmed

| dysmorphism; by PCR) ubr7 Number microcephaly sacral caudal remnant Ectodermal dysplasia and Xq28 IKBKG 300291 Fetal lethal or Heterozygotes not affected Yes, severe, with gradual T cells AR immune deficiency 154,542,211 Hypomorphic variants Dysglobulinemia. elimination of mutant T cells | uy2020 July with NF Kappa B Recurrent infections, activation Osteopetrosis Abnormal teeth Ectodermal dysplasia Xq13.1 EDA 305100 Defective skin, hair, nails Variable severity No WBC AR

| 61,616,085 Akin to tabby mouse & teeth Skewing correlated with EEISi MEDICINE in GENETICS missense, nonsense Variant interferes with disease severity deletion, & splice junction rounding of cells by the variants cell membrane Epileptic encephalopathy early Xp21.3 ARX 308350 Spasms without brain Milder than males ND infantile, 1 25,003,693 malformations MIGEON EEISi MEDICINE in GENETICS MIGEON Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Epileptic encephalopathy Xp22.13 CDKL5 300672 Infantile seizures, global Milder than males No skewing WBC AR early infantile, 2 18,425,604 deletions delay subtle dysmorphic However, most features; most die early heterozygotes affected… Males may die in utero? (32 deletions in females vs. 3 in | oue22 Volume males [Decipher]) Epileptic encephalopathy Xp22.13 CDKL5 300672 Some overlap with Rett; Females less severe More apt early infantile, 2 18,425,604 missense profound retardation and to have hand stereotypies EEG abnormalities than males AR | Epileptic encephalopathy, early Xq11.1 Collybistin 300429 Heterozygotes not affected No, but manifesting WBC ubr7 Number infantile, 8 63,634,966 ARHGEF9 unless skewed X-inactivation requires complete skewing Manifesting females all have (mutant gene active) chromosome Translocation or Speculation: skewing in deletion; 2 females with brain but not in blood |

uy2020 July autism and intragenic deletions and no skewing Epileptic encephalopathy, early Xq22 PCDH19 300088 Not affected ID, Infantile seizures ND infantile, 9 100,291,643 Mosaic males are affected Autism However, cellular interference thought to play a role Epileptic encephalopathy, early Xq11.23 SLC35A2 300896 See CDG2M infantile, 22 48,903,182 Fabry disease Xq22.1 GLA 301500 Progressive heart & kidney Attenuated No Skin GLA 101,397,790 disease Females express because not fibroblast clones a high uptake enzyme Fanconi anemia Xp22.31 FANCB 300514 Bone marrow failure, No affected females Yes, extreme WBC AR 14,690,862 predisposed to cancer Focal dermal hypoplasia Xp11.23 PORCN 305600 Fetal lethal ID; skin atrophy & Microdeletions associated WBC AR 48,508,991 Loss of function Mosaic males survive, and pigmentation; multiple with severe skewing have abnormalities, like papillomas; abnormal digits, Point variants not skewed females (10% of affected) striated bones; lobster claw Focal dermal hypoplasia Xp11,23 PORCN (missense) 305600 2 nonmosaic survivors; Random XI, but No WBC AR 48,508,991 Missense variant inherited asymptomatic from mother Fragile X syndrome Xq27.3 FMR1 300624 XLID; congenital Variable, milder Yes, slight (full mutation) WBC, skin FMR1 147,911,918 anomalies fibroblasts methylation Glycogen storage disease Xp22.13 PHKA2 306000 No PHK activity in liver Not usually affected No Skin fibroblasts PHK activity 1Xa1 GSD9A1 18,892,297 Complete loss of & RBCs function Yet mildest form of glycogen storage disease Glycogen storage disease Xp22.13 PHKA2 306000 No PHK activity in liver; Heterozygotes not affected ND 1Xa2 GSD9A1 18,892,297 Missense enabling partial even milder than above function Hemolytic anemia Xq28 G6PD 305900 Chronic anemia High dosages of primaquine; Yes, slight with age RBC, WBC G6PD 154,531,389 Rx for malaria cause hemolysis, if enough cells

are mutant ARTICLE REVIEW Hunter syndrome (MPS2) Xq28 IDS 309900 Mucopolysaccharidosis Rarely affected No Skin IDS 149,505,353 unless skewed fibroblast clones Hydrocephalus, X-linked (due Xq28 L1CAM 307000 Only males affected Heterozygotes not affected ND to aquaductal stenosis) allelic 153,861,513 ID, spastic paraplegia with MASA Some have clasped thumb MASA syndrome Xq28 L1CAM 303350 Spastic paraplegia, Mild ID, abducted thumbs ND SPG1 153,861,513 same variants aphasia, ID, abducted thumb, but no congenital hydrocephalus Family can segregate MASA or hydrocephalus

1161 phenotypes Hypophosphatemic rickets Xp22.1 PHEX 307800 Short stature; rickets; Heterozygotes variably ND 22,032,324 bone deformities affected 1162 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Ichthyosis Xp22.31 STS 308100 Extensive body ichthyosis, Late corneal opacities No (point variant) Skin STS & G6PD 7,147,289 corneal opacities Expressed from XI fibroblast clones Escape gene; 1/3 activity of XA Immunodeficiency 33 Xq28 NEMO variants disrupt 300636 Infections limited to Heterozygotes not affected ND 154,542,239 leucine zipper mycobacteria Incontinentia pigmenti IP2 Xq28 NEMO 308300 Fetal lethal usually; milder Cell death causes rash along Yes, severe skewing toward Blood, WBC, HPRT & G6PD Allelic with 154,542,239 IKBKG variants (hypomorphic) IKBKG Blaschko lines wild type, even with milder Skin immunodeficiency 33 Usually deletions variants lead to Abnormal hair and teeth variants that permit male fibroblast clones eliminating NF Kappa B osteopetrosis in males only Females with hypomorphic survival activation IKBKG variants do not have osteopetrosis Immunodysregulation, Xp11.23 FOXP3 304790 Immunological disorder; Heterozygotes not affected ND polyendocrinopathy, and 49,250,435 (Scurfin) diabetes mellitus, enteropathy (IPEX) Scurfy in mice dermatitis and enteropathy, onset in infancy; death by 2 years unless treated by immunosuppression and blood cell transplantation; absence of islets of Langerhans; presents as severe diarrhea Kabuki syndrome 2 Xp11.3 KDM6A or UTX 300867 ID Like males If deletion, then skewed; if WBC AR 44,873,174 (mediates removal of Dwarfism, Kabuki facies, Some say females less severe variant, not skewed trimethylation of histone skeletal abnormalities; than males—perhaps due to Escapes XI H3, at HOX promoters, UTY protects skewing disfavoring deletions demethylates H3K27; Escape may not protect methylates H3K4) females more than males as males also have an allele (UTY) on their Y chromosome Keipert syndrome Xq26.2 GPC4 301026 Craniofacial Carrier females are clinically Yes, severe in blood WBC AR Allelic with 133,300,102 Missense variants dysmorphisms; foot and unaffected, because all are Simpson–Golabi–Behmel Duplications cause hand abnormalities; >90% skewed toward syndrome Simpson–Golabi–Behmel mild intellectual disability wild type syndrome Kelly–Seegmiller syndrome Xq26.2 HPRT 300323 Uric acid stones leading to Heterozygotes not affected No WBC (gout, X-linked) 134,460,164 308000 gouty arthritis oue22 Volume Allelic with Lesch–Nyhan (partial, <95% deficiency) syndrome Lesch–Nyhan syndrome Xq26.2 HPRT 300322 ID, Heterozygotes not affected Yes, severe (blood) RBC, WBC, skin HPRT, G6PD Allelic with X-linked gout 134,460,164 308000 spastic cerebral palsy, No in skin because of gap fibroblast

| (>98% deficiency) uric acid stones, self- junctions clones ubr7 Number destructive biting Lissencephaly & agenesis of the Xq22.3-q23 DCX 300067 ID, brain malformation Mild epilepsy (subcortical No Blood AR corpus callosum 111,293,778 due to neural migration band heterotopia) or normal defect seizures | uy2020 July Lowe syndrome Xq26.1 OCRL1 309000 ID; cataracts; rickets; Heterozygotes not affected (100%) in one manifesting WBC AR 129,540,258 aminoaciduria heterozygote unrelated to variant Severe systemic lupus Xp22.2 TLR7 300365 Rarely affected, Females 9 times frequency ND

| erythematosis 12,867,071 except if XXY of males Escape from inactivation in EEISi MEDICINE in GENETICS all females; B lymphocytes, monocytes and plasmacytoid dendritic cells Lymphoproliferative Xq25 XIAP inhibitor of apoptosis 300079 Pancytopenia, Usually heterozygotes not Yes, in hematopoietic cells WBC AR syndrome 2 XLP2 123,859,811 BIRC4 splenomegaly, affected pancolitis Occasionally female affected due to skewing toward MIGEON mutant cells EEISi MEDICINE in GENETICS MIGEON Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Lymphoproliferative syndrome Xq25 SH2D1A 308240 Severe immunodeficiency No reported affected females Carrier female had WBC AR XLP1 (Duncan disease) 124,346,281 300490 especially after EB virus (probably because both complete skewing toward infection; severe or fatal skewing plus exposure to EB wild type in NK cells but not mononucleosis; acquired virus needed) in T or B cells

| hypogammaglobulinemia; oue22 Volume hemophagocytic lymphohistiocytosis (HLH), and/or malignant lymphoma MED12 HOPA | Mediator complex subunit 12 Xq13.1 or 300188 ID plus Infrequent & milder See below ubr7 Number MED12 71,118,595 Transcriptional activator tall stature Allelic with Lujan–Fryns & repressor (all hemizygous missense syndrome (309520); Ohdo Different variants cause variants; different syndrome (300895); different syndromes missense variants in | – uy2020 July Opitz Kaveggia syndrome Missense variant same gene) (305450) ID plus macrocephaly; hypotonia; absence of corpus callosum Lujan–Fryns Syndrome Xq13.1 MED12 or HOPA point 309520 Marfanoid habitus; long, Heterozygotes not affected ND 71,118,595 variant in exon 22 narrow face; moderate ID; Ohdo syndrome Xq13.1 MED12 or HOPA 300895 Blepharophimosis; ptosis; Heterozygotes not affected ND 71,118,595 Missense variants cryptorchidism; ID Opitz–Kaveggia syndrome Xq13.1 MED12 or HOPA 305450 ID; macrocephaly; Much milder; hypertelorism; Variable; Four of 18 WBC AR & FMR1 71,118,595 Missense variants hypotonia & imperforate normal IQ heterozygotes showed C-T transition in exon 21 anus; partial or complete significant skewing but in absence of the corpus different directions callosum; often cryptorchidism Melnick–Needles syndrome Xq28 FLNA 309350 1 of 4 otopalatodigital Most affected have much Yes, likely WBC AR See OPD1 154,348,530 syndromes caused by milder phenotype; skewed toward the normal variants in FLNA; most are mild deformity of bones allele because of cell severe; prenatal mortality selection or perinatal death Severe congenital abnormalities Menkes syndrome Xq21.1 ATP7A 309400 Copper deficiency Heterozygotes not affected Yes, severe WBC, AR Allelic with occipital horn 77,910,655 Truncation Caveat: 15-kb deletion lymphoblasts, syndrome & spinal muscular skin fibroblasts atrophy Methylmalonic acidemia Xq28 HCFC1 309541 Nonsyndromic ID Normal IQ Yes, severe WBC Also referred to as XLMR 45 153,947,555 Host cell factor C1 Highly skewed XI Data not shown 300019 Missense Microophthalmia syndrome 2 Xp11,4 BCOR 300485 (See OFCD) 300166 Male lethal Congenital cataract, ND (MCOPS2) 40,051,245 Premature stop codons microopthalmia Allelic with OFCD Cardiac abnormalities

Dental abnormalities ARTICLE REVIEW Microphthalmia, syndromic 7 Xp22 HCCS 300056 Male lethal Wide spectrum ranging from Severe; complete or WBC AR, MAOA, PGK (MCOPS7) 11,111,331 microdeletions Due to OXPHOS defect asymptomatic to corneal moderate (>80%) skewing FMR1 opacity; Favoring normal allele (in microphthalmia; blood cells) linear skin defects; microcephaly; cardiac defects Monoamine oxidase A Xp11.3 MAOA 300615 Mild ID; aggressive Heterozygotes not affected ND deficiency (Brunner syndrome) 43,654,906 impulsive behavior Muscular dystrophy, Xp21 DMD 310200 Muscular dystrophy Only when unrelated skew No WBC AR Duchenne 31,119,218 Mild ID favors mutant cells Muscular dystrophy, Xq28 EMD 310300 Muscular dystrophy; No affected females ND Emery–Dreifuss 154,379,235 heart arrhythmias MTM1

1163 Myotubular myopathy XQ28 300415 Respiratory failure during Asymptomatic, or mild NO or ND 55:45 method 150,673,142 1st year; severe hypotonia weakness Histology (I think) looking not presented Some females skewed and for ragged fibers 1164 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay symptomatic One female skewed 70:30 in muscle, and 55:45 in blood Neurodegeneration with Xp11.23 WDR45 (all de novo) 300894 Fetal lethal, Static encephalopathy of Only rare, severely skewed WBC AR brain 49,074,432 Most truncating or Mosaics survive to be childhood with toward wild type females iron accumulation (NBIA5) partial deletion affected neurodegeneration in survive to manifest adulthood; parkinsonism; dystonia; dementia Xp11.23 WDR45 300894 Occasional missense Infantile spasms; Skewed X-inactivation 2:98 WBC AR? 49,074,432 BPAN variant variant or germline developmental delay; ID; in 11-year-old female mosaicism, but most males absent to limited language; Several older females with die in utero Parkinson disease and normal allele preferentially dystonia develop with age inactivated Neurite extension & Xq13.3 NEXMIF formerly KIA2022 300524 XLID Less severe No WBC Methylation? migration Factor 74,732,855 See XLID98 36–64% Night blindness (congenital) Xp11.4 NYX (nyctalopia) 310500 Myopia and night 14 daughters of 9 affected ND type 1A CSNB1A 41,447,459 blindness; rod males were not affected function absent However, some heterozygotes are and may reflect skewing—or are homozygous for the variant Night blindness (congenital Xp11.23 CACNA1F 300071 Nonprogressive retinal 6 obligate carriers had no ND stationary incomplete) type 2A 49,205,062 disorder with myopia and symptoms nystagmus No deterioration Nystagmus 1 (congenital) Xq26,2 FRMD7 310700 Infantile, periodic, 53% of carriers are affected Findings not interpretable Actual data AR 132,074,925 alternating Some have skewed X- Perhaps wrong tissue not shown inactivation analyzed One normal skewed; other normals at 50–60% Four affected skewed; two nonskewed Ogden syndrome Xq28 NAA10 300855 Delayed psychomotor 1 severe female (with loss of 4/4 nonaffected WBC AR Some variants cause 153,929,224 development; dysmorphic function variant; another Heterozygotes have 90- microphthalmia syndrome facial features; scoliosis, mild ID 100% skewing oue22 Volume (309800) and cardiac dysfunction Wide spectrum depending on with long QT syndrome nature of variant; females with same variant as males are usually milder BCOR | Oculofaciocardiodental Xp11.4 null 300166 Death in utero OFCD Some skewing toward ubr7 Number syndrome 40,051,245 Early onset cataracts wild type Microphthalmia syndrome 2 Radiculomegaly of canine teeth Cardiac septal defects |

uy2020 July Facial dysmorphism X-linked BCOR-related Xp11.4 BCOR variant 300485 Microphthalmia syndrome Heterozygotes not affected 100% skewing syndrome 40,051,245 C to T transition Severe microphthalmia Lenz microphthalmia Some variants have no eye

| abnormalities, but MR EEISi MEDICINE in GENETICS Orofaciodigital syndrome Xp22.2 OFD1 (CXORF5) 311200 Fetal lethal Malformations of face & No human gene escapes XI WBC AR (OFD1) 13,734,712 A ciliopathy digits; polycystic kidneys In mice no escape and Allelic with neonatal mouse females die Simson–Galabia–Beheld of polycystic kidneys syndrome 2 & Joubert syndrome 4-bp deletion in OFD1 Mother (not affected) has causing frameshift random XI but affected MIGEON daughter is skewed toward mutant allele EEISi MEDICINE in GENETICS MIGEON Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Joubert syndrome 10 XP22.2 OFD1 300804 Ciliary dysfunction Heterozygotes not affected ND Allelic with 13,734,712 Small deletions Hypotonia Simpson–Golabi–Behmel, and Cerebellar ataxia OFD1 – – OFD1

| Simpson Golabi Behmel Xp22.1 300209 One family of 9 males; Heterozygotes not affected ND oue22 Volume syndrome type 2 13,734,712 4-bp deletion most die early but one had Allelic with OFD1 severe ID, facial dysmorphisms, obesity, & repeated respiratory

| infections; respiratory cilia ubr7 Number disorganized and uncoordinated Oropalatodigital syndrome 1 Xq28 FLNA 311300 Cleft palate, conductive Some mild symptoms No, but skewing WBC AR 154,348,530 Mildest of spectrum hearing loss; mild skeletal causes manifestation |

uy2020 July abnormalities & renal failure Oropalatodigital syndrome 2 Xq28 FLNA 304120 Disabling skeletal Milder symptoms, some facial 154,348,530 Gain of function variants anomalies, variable brain, dysmorphism cardiac, intestinal anomalies Melnick–Needles syndrome Xq28 FLNA 309350 Fetal lethal Skeletal dysplasia Yes? Skewing in blood WBC 154,348,530 Most severe toward normal in 3 affected heterozygotes, but FLNA interacts with AR so assay may not be valid Frontometaphyseal dysplasia Xq28 FLNA 305620 Frontal bone overgrowth, Normal, or mild hyperosteosis ND 154,348,530 scoliosis, facial dysmorphism; increased bone density; occasional renal abnormality Ornithine transcarbamylase Xp11.4 OTC 311250 Urea cycle disorder; 85% are symptomatic with No, but skewing in liver, not WBC & Liver deficiency 38,352,527 males die in infancy of hyperammonemia WBCs, corresponds with severe disease unless 20–30% activity not enough severity treated PDC deficiency Xp22.12 PDHA1 312170 a) Neonatal lactic acidosis; Dysmorphic features; No, but skewing determines WBC AR 19,343,892 pyruvate dehydrogenase encephalopathy; brain microcephaly; moderate or severity of phenotype complex, E1-ɑ malformations; early death severe psychomotor delay; polypeptide 1 b) Infantile or childhood- spastic di/quadriplegia & onset Leigh syndrome epilepsy (cortical atrophy, cyst c) Milder relapsing & corpus callosum agenesis); disorder of ataxia dystonia all heterozygous; more severe and peripheral neuropathy variant than in males Missense variants are milder Pelizaeus–Merzbacher Xq22.2 PLP1 point variant 312080 Myelin leukodystrophy No symptoms or milder; During CNS development, WBC, AR 103,776,505 Often duplications Spastic diplegia Rare female affected due to oligodendrocytes with lymphoblasts of Xq22.2 skewing toward mutant cells severe PLP1 mutant alleles Some mild affected have no are negatively selected EIWARTICLE REVIEW skewing because variant not (apoptosis) in favor of wild severe enough to skew type cells, with cell type specific skewed XI PIH1D3 Xq22.3 PIH1D3 formerly Cxorf41 300933 Primary ciliary dyskinesia; Heterozygotes not affected ND 107,206,610 Expressed primarily in testes nonsyndromic ODA; Normal fertility respiratory infections; chronic otitis; infertility with mutant sperm Phosphoribosyl Xq22.3 PRPS1 300661 Hyperuricemia; gout; His mother had gout, uric ND pyrophosphate 107,628,423 Gain of function deafness and neurological acid stones and hearing loss synthetase 1 spectrum misfunction Charcot–Marie–Tooth Xq22.3 PRPS1 311070 Peripheral neuropathy; Not affected or milder Variable skewing consistent WBC AR 107,628,423 Reduced expression deafness; visual with phenotype 1165 impairment; no increased uric acid 1166 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Arts syndrome Xq22.3 PRPS1 301835 ID; hypotonia; ataxia; Milder but continuous Variable skewing consistent WBC AR 107,628,423 Reduced expression hearing impairment and spectrum depending on with phenotype optic atrophy extent of skewing DFNX1 Xq22.3 PRPS1 304500 Deafness Spectrum of phenotypes ND 107,628,423 Missense variant Usually milder 40–70% reduced activity Protoporphyria (X-linked Xp11.21 ALAS2 300752 RBC porphyria 11 females vary in phenotype No selection, but skewing Blood DNA AR & ZMYM3 erythropoietic) 55,009,054 Increased activity with skewing of XI correlated influences phenotype gain of function with degree of severity Example of no X-linked dominant disease Raynaud–Claes syndrome Xp22.2 CLCN4 300114 Severe ID & epilepsy Milder Not shown; WBC ?? Poor study 10,156,944 Chloride/hydrogen ion Impaired language No obvious selection exchanger truncated and missense frameshift Renpenning syndrome Xp11.23 PQBP1 300463 MR; short stature, Unaffected, but skewed XI Highly skewed WBC AR, FMR1 48,897,861 Polyglut binding protein 1 microcephaly Retinitis pigmentosis 3 Xp11.4 RPGR 300029 Inherited choroidal retinal All heterozygotes have ND 38,269,162 degeneration; destroys rod tapetal-like retinal reflex; Loss of photoreceptors; some heterozygotes are function; become blind affected—usually milder, but hot spot in variable; rarely legally blind exon 15 X-linked cone–rod dystrophy Xp11.4 RPGR 304020 Progressive loss of vision Not affected, but detectable ND 38,269,162 by visual testing variants in alternate exon 15 Syndromic retinitis Xp11.4 RPGR 300455 RP3 with sinorespiratory Often affected, but milder ND pigmentosa 38,269,162 infections, with or without deafness Rett syndrome Xq28 MECP2 312750 Fetal lethal; MR; arrested development; No, unless large deletion; WBC AR 154,021,572 point variant 300005 mosaic males have Rett impaired speech; Blood DNA does not always syndrome; some males handwringing reflect brain DNA without obvious mosaicism survive; severity dependent on oue22 Volume mosaicism & variant Lubs XLID Xq28 MECP2 duplication 300260 Affected males have Rett Unaffected because of Extreme skewing WBC AR Allelic with Rett syndrome 154,021,572 phenotype; moderate to extreme skewing severe ID; seizures

| Sick sinus syndrome Xq28 MECP2 deletion Not Autonomic NS affected in Milder symptoms Extreme skewing in WBC AR ubr7 Number 154,021,572 (0.6 deletion effecting yet given two brothers unaffected mother TDR) Simpson–Golabi–Behmel Xq26.2 GPC3 312870 Congenital malformations Rare; usually unaffected or No; skewing toward mutant ? syndrome type 1 133,535,744 Duplication of GPC3 & & overgrowth much milder produces symptoms | uy2020 July GPC4 produce some ID, macrocephaly, Rarely affected; Normal females not skewed affected females, but cleft palate Female with a small Xq26 skewing toward microduplication is affected; mutant needed she has random XI IL2RG | SCIDX1 Xq13.1 300400 B- & T-cell Heterozygotes not affected Yes, extreme T & B cells Cell count EEISi MEDICINE in GENETICS Severe combined 71,107,403 immunodeficiency immunodeficiency CIDX1 Xq13.1 IL2RG 312863 Milder allele of SCIDS Heterozygotes not affected Yes Predominantly AR 71,107,403 affects T cells, Tonne–Kalscheurer syndrome Xq13.2 RLIM 300379 Global developmental Heterozygotes not affected All 4 females with mild WBC AR 74,582,975 RFN12 delay; ID; subtle facial unless severe skeletal anomalies were dysmorphism; multiple loss of function extremely skewed (not congenital anomalies shown), and normal females MIGEON autism; severe feeding also skewed Direction of problems skewing not shown EEISi MEDICINE in GENETICS MIGEON Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay Thrombocytopenia Xp11.23 WAS 313900 Decreased number of Rare, presumably due to Reported as random but WBC AR Allelic with Wiskott–Aldrich 48,683,752 hypomorphic alleles platelets; bleeding chance skewing results not interpretable tendency Wiskott–Aldrich syndrome Xp11.23 WAS 301000 Deficiency of B & T cells, No affected females Yes, severe T, B cells & AR

| 48,683,752 severe loss of function leukocytes & granulocytes oue22 Volume thrombocytes XLID 1 & 18, 78 Xp11.2 IQSEC2 300522 ID nonsyndromic Some have learning ND, escapes XI Allelic with 53,225,783 Nonsense & duplications disabilities 1Q motif and SEC7 Domain

| 18M,19F XLID ubr7 Number IQ Motif and SEC7 Domain Xp11.22 IQSEC2 300522 ID nonsyndromic; 95% Milder ID 70% epilepsy No, 1 severely affected Blood DNA AR 18M,19F 53,225,783 (Shapes dendrite have epilepsy without seizures—all de novo female favoring XLID morphology) Truncating variants reduce axon 4/5 affected had random XI mutant allele allelic with XLIDR 1, 18 and 78 variants length in mice; de novo or 1 skewed 2 nonaffected Human gene escapes XI, | uy2020 July maternal carriers had random but not mouse gene inactivation XLID 12 Xq25 THOC2 300395 Mild–moderate ID Heterozygotes not affected Also called THOC2 XLID 123,600,562 Speech delay Neurological developmental defect XLID 15 Xq24 CUL4B 300354 ID (IQ 29–54), short Rarely mild tremor, tics Yes, severe WBC Cullin Ring 120,524,588 stature macrocephaly, Mice die due to PXI Cabezas type hypogonadism (small Obligate heterozygotes have testes), tremor, large hands abnormal gait some learning disability XLID Turner Xp11.22 HUEW1 309590 Moderate to profound ID, Heterozygotes not affected Yes & no: severe favoring WBC AR 53,532,095 E3 ubiquitin ligase global delay with wild type in some females 300697 macrocephaly with microduplications Microduplications nonsyndromic Xp11.22 HUEW1 309590 Moderate to profound Heterozygotes not affected 53,532,095 Missense variants XLID; short stature; speech codes E3 ubiquitin ligase pathology; small hands & feet Xp11.22 HUEW1 309590 No affected males seen Females with dysmorphic Severe skewing favoring 53,532,095 De novo loss of function XLID; craniostenosis; Chiari mutant in affected females malformation XLID Claes–Jensen Xp11.22 KDM5C/JARIDC 300534 Short stature; Milder Yes, severe favoring wild WBC AR 53,176,276 314690 microcephaly; type in 4 unaffected Also, SMCX abnormal facies; heterozygotes developmental disability XLID Houge type Xp22.2 CNKSR2 301008 Delayed psychomotor Mild learning disability or Not shown, but 2 WBC (MRXSHG) Deletions; frameshifts; development; poor verbal nonaffected manifesting heterozygotes truncating variants skills; microcephaly; focal Speculation that skewed XI had 56:43 and 20:80 seizures prevents severe effects in XI ratios brain, but not shown, nor is CNKSR2 is only expressed in it needed brain tissue PHF8 AR XLID Siderius Xp11.22 300263 ID; abnormal facies; cleft Heterozygotes not affected Yes, severe favoring wild WBC ARTICLE REVIEW 53,936,679 Microdeletion (470 kb) palate/lip type in unaffected mother, XLID 90 Xq13.1 DLG3 300850 Moderate to severe Heterozygotes are usually not Majority of heterozygotes 70,444,834 Truncating nonsyndromic ID affected have random XI Skewing influences phenotype XLID 98 Xq13.3 NEXMIF (KIAA2022) 300524 Severe ID; poor speech Usually not affected unless Normals not studied (one WBC AR 74,732,855 Hypomorphic loss of postnatal growth truncating variants inversion showed skewing) function retardation (see below) 1 affected female not Strabismus skewed (73:27) Xq13.3 NEXMIF 300524 NA 14 females with 6/7 had random XI WBC ? Data not shown 74,732,855 (KIAA2022) intractable epilepsy, 1/7 (the most severe) had Heterozygous truncating milder ID completely skewed XI variants—all loss of favoring mutant cells

1167 function 1168 ARTICLE REVIEW Table 1 continued X-linked disease X Map Gene OMIM Phenotype: males Phenotype: females Cell selection Tissue XI skewing assay XLID 99 Male restricted Xp11.4 USP9X 300919 ID, hypotonia, aggression, Female carriers identified and ND (MRXS99F) 41,085,419 Nontruncating missense thin corpus callosum; loss none affected USP9X escapes XI in some variants, no effect on of hippocampal- tissues, not in others catalytic activity dependent learning & memory XLID 99 Female restricted Xp11.4 USP9X 300968 Male lethal MR; short; choanal atresia; Affected females may be WBC AR 41,085,419 30072 Truncating variants are heart defects; polydactyly; skewed >90% but test does Point variants leading to lethal in males hearing loss; not show direction; USP9X truncation skin pigmentation (Blaschko) escapes XI in some tissues De novo loss of function variants XLID 102X Xp11.4 DDX3X complete loss of 300958 LOF lethal (Decipher shows LOF causes MR, No 41,333,307 function 300160 loss of males) spasticity, ASD DDX3X escapes XI Heterozygotes with Homolog on Y hypomorphic variant are not affected Xp11.4 DDX3X Occasional males have No disease ND 41,333,307 Hypomorphic variants nonsyndromic ID XLID 106 Xq13.1 OGT 300997 IQ 49–61; facial Females normal but highly No reference provided 71,533,103 Missense dysmorphisms skewed X-inactivation In mice, if maternal allele Mild spastic diplegia plus mutant then other congenital embryonic lethal abnormalities Embryonic lethal (mice) XLID 106 Xq13.1 OGT 300997 Usually only males Twin sisters Each had 93:07 Direction of WBC AR 71,533,103 Missense XLID plus some facial skewing not known dimorphisms XLID 107 Xq24 Cxorf56 301013 5 males: Moderate ID, Milder Normal WBC AR 119,538,148 301012 Long narrow face 1 female with no skewing Significantly skewed Frameshift variant (57%) but nonaffected (76–93%) carriers were skewed XLID Wilson–Turner Xq13.2 HDAC8 300269 ID, microcephaly Milder Yes, extreme WBC AR See Cornelia de Lange 5 72,329,515 Point variants craniofacial deformities The X-linked diseases in this table are disorders with available information about heterozygous females. They are listed with their disease name, their X map locus (the location of the gene on the X chromosome, including its 5’ start site, from OMIM). These data are followed by the symbol for the variant gene, the protein that is deficient and the nature of the variant if known. In each case, although the phenotype is variable, the most com- mon one is described. Cell selection favors cells expressing the normal allele, unless otherwise indicated. In all cases chance skewing, that is skewing unrelated to the variant, influences the phenotype. Allelic disorders are indicated in bold. oue22 Volume AR androgen receptor, ASD autism spectrum disorder, ID intellectual deficiency, LOF loss of function, SCIDS severe combined immunodeficiency syndrome, XLID X-linked intellectual deficiency, WBC white blood cells. | ubr7 Number | uy2020 July | EEISi MEDICINE in GENETICS MIGEON MIGEON REVIEW ARTICLE metabolic function from the cells that transcribe the normal of genes in related pathways on the ultimate phenotype is allele. meager, but suggests that we need to be aware of the potential The crucial protein is provided in one of two ways. Either effect of other relevant genes on any variant. Although the cells that can make it transfer it to the deficient cells, or, if Table 1 includes only one known instance of digenic X this cell-to-cell transport does not take place, the lack of variants (Dent disease 2), one expects there will be more. The functional protein may cause the deficient cells to divide less effect of digenic variants leading to Dent disease are efficiently, and so they are eventually overgrown by the cells ameliorated in the heterozygote, who carries both variants that make the normal protein. Yet, in various tissues, cells on the same X chromosome, as these abnormal cells are differ in their capacity to transfer gene products and so there strongly disfavored (Table 1).8 In this case, heterozygotes are may be differences within body tissues in the ability of the much less severely affected than hemizygous males because of normal cell to share, or the abnormal cell to survive12 (Fig. 1, the strong cell selection against cells expressing the two Table 1). variants simultaneously.

FEMALES ALMOST ALWAYS HAVE LESS SEVERE EFFECT OF SEX AND X-INACTIVATION ON PHE- MANIFESTATIONS OF X-LINKED DISEASES NOTYPE IN X-LINKED DISORDERS For most X-linked deleterious variants, the manifestations are As I learn about why some heterozygotes express their less severe in females than males. The mix of normal and variants, yet others with the same variant do not, I more fully abnormal cells moderates females' disease. Yet, there are appreciate the nuances of disease processes and the intricacy disorders in which the variant is so lethal that most males of the interdependence between the type of cell, its response with severe deficiency of the gene product die in utero. to abnormal gene products, and the nature of the disease Because the only survivors are females or mosaic males, who variant. Table 1 shows the effect of pathogenic variants of X- also have a mix of variant and normal cells, they are the ones linked genes in males and females. For almost all of the with nonlethal manifestation of the disorder. X-linked disorders listed, females have less severe clinical manifesta- diseases, such as incontinentia pigmenti, or orofacial digital tions. Table 1 also documents the variables that determine if syndrome type 1, occur only in females or mosaic males.13 an X chromosomal variant is manifested or not, that is, if products are shared or if normal cells have a selective SOME FEMALES ARE MANIFESTING advantage. The severity of the phenotype is most often HETEROZYGOTES attributable to the nature of the variant. Does it completely Many factors determine if a heterozygote manifests her eliminate the gene’s function, or does it allow some gene mosaic variant. Our knowledge of the effect of second variants product to be produced? Variants that disable an essential

Variable mosaicism Random X in affected tissues Blastocyst inactivation

Female

Male Phenotypic Selective Mosaic variability male advantage of cells with normal X active

Cell with variant allele active Cell with normal allele active

Fig. 1 Comparing the effect of a single pathologic variant in females and males. Adapted from Fig. 1 of Franco B, Ballabio A. Curr Opin Genet Dev. 2006;16:254–259, with permission of authors. In females: On average, the ratio of the two cell types (expressing normal or variant alleles) is approximately 50:50. However, the ratio may differ because of chance, or a selective disadvantage for cells expressing the variant. Extreme divergence from the 50:50 ratio, known as skewing of XCI, may differ from tissue to tissue, and among individuals influencing the severity of the phenotype. Cell selection usually takes place only in cells which express the variant and which do not receive the essential gene products from the normal cells that make them. In males:anX- linked variant is expressed in every cell. The exceptions are males with somatic mosaicism: like females, mosaic males will express both variant and normal allele, and the phenotype depends on the admixture of variant and normal cells.

GENETICS in MEDICINE | Volume 22 | Number 7 | July 2020 1169 REVIEW ARTICLE MIGEON protein completely are more often seen in females, as males abnormal cells may never enter a tissue. In cases of whose only gene is nonfunctional are lost in utero, immunodeficiencies, like Wiskott–Aldrich syndrome, the unless other genes can substitute for it. On the other hand, growth disadvantage is immediate; the mutant B cell variants with some residual function may affect only males. In precursors never leave the bone marrow (Table 1).8 both cases, the female phenotype is less severe, as she has Unfortunately, sometimes it is the variant cell that has the some normal cells that carry out the essential function. selective advantage. For reasons not yet understood, heterozygotes with the variant causing adrenoleukodystro- EFFECT OF SHARING GENE PRODUCT BETWEEN phy slowly lose their population of wild type cells.18 CELLS Therefore, as they age, they usually manifest some Because it is largely unknown, Table 1 does not include the symptoms of the disease. Adrenoleukodystrophy is the only quantity of gene product that must be provided to a cell to known X-linked disease where the variant allele has a replace that lost through a variant. In most cases 50% activity selective advantage. X-linked variants that slow the growth is more than enough, and for many genes, even smaller of the expressing cells usually protect females from amounts of product will suffice. This readily explains why manifesting them. If one examines the cells from these many X-linked disorders never affect women. For example, heterozygotes, one sees highly skewed patterns of X- less than 5% of the enzyme HPRT can alter the phenotype inactivation in the expressing tissues: eventually, the X with from severe hyperuricemia, seen in Lesch–Nyhan males, to the variant will always be silent (that is, always on the gout. Lesch–Nyhan heterozygotes rarely express any features inactive X). Females carrying pathologic variants that of the syndrome, including gout. In most of her tissues the produce X-linked mental retardation often have X- product of the HPRT reaction, inosinic acid, is transferred inactivation patterns that are highly skewed favoring from her cells that synthesize it, to those that cannot, through expression of the wild type gene, protecting them from ill gap junctions, present in all cells of the body except blood effects of their variant.19 In such women, the cells that cells.14 express the variant gene are disfavored. Cell sharing also occurs in women who are heterozygous for variants causig X-linked lysosomal diseases. Lysosomes MANIFESTING HETEROZYGOTES contain many enzymes that break down proteins and lipids. With so many mechanisms available to protect females with Variants in the genes that encode these enzymes cause an X-linked pathologic variant, one wonders why some diseases by the accumulation of undegraded material within heterozygotes manifest any symptoms of a disease. As the lysosomes of affected individuals. Fortunately, the mentioned previously, if the variant is so functionless that it deficient cells of the heterozygote can take up the enzyme is lethal to fetal or newborn males, then females with a single secreted by the normal cells through a process called mutant allele are the only ones that can have the disease. As endocytosis. Therefore, potential manifestations in carriers Table 1 indicates, the severity of the variant can determine if of variants of lysosomal enzymes encoded by the X females express the variant or not. chromosome are generally ameliorated by the transfer of Occasionally, females are the ones to manifest a disease these enzymes from the cells that can make them to those that because the variant allele interacts with the normal one, cannot.15 undergoing a process called cellular interference. The most well defined example of this is the craniofrontonasal EFFECT OF CELL SELECTION IN MOSAIC FEMALES syndrome, caused by a deficiency of Ephrin-B1 (EFNB1).20 Because they lack gap junctions, the leukocytes from Other members of the ephrin family of proteins can substitute Lesch–Nyhan heterozygotes do not receive the inosinic acid for a deficiency of EFNB1 in males with the deleterious made by their normal counterparts. Fortunately, the lack of variant, and as a result, they have minimal clinical symptoms. inosinic acid slows the rate of cell division; the normal cells Heterozygotes, however, have a mixture of mutant and wild (because the variant is on their inactive X) eventually replace type cells; for reasons not yet understood, it seems that such the deficient ones. As a consequence, heterozygous mothers mixtures do not permit ephrin substitutes, and consequently, and sisters of Lesch–Nyhan males have only normal blood females have a deficiency more severe than that in males, who cells, and in other tissues, their mutant cells share the gene can substitute one ephrin for another. It is heterozygosity, not products provided by their normal cells.16 It takes about ten the complete loss of function, that produces the severe years for all their abnormal red cells to be replaced17 because disorder. It is the patchwork or mosaic loss of EFNB1 that in this case, the selective advantage of the normal allele is disturbs tissue boundary formation at the developing coronal relatively small. suture. Several forms of infantile epilepsy also show similar The rate of loss of deficient cells can be slow or fast cellular interference, but fortunately no other examples depending on the degree to which the variant is disadvanta- are known. geous. When selection is intense, that is, when it severely Yet, there are females who express an X-linked pathogenic disfavors the cells that express the variant, heterozygous variant, even though most carriers of pathogenic females benefit, as they rapidly lose all their mutant cells. variants in similar genes do not. For example, females Sometimes the loss of variant cells occurs so early that with Fabry disease, caused by lack of the lysosomal enzyme

1170 Volume 22 | Number 7 | July 2020 | GENETICS in MEDICINE MIGEON REVIEW ARTICLE

Table 2 Factors influencing expression of X-linked variant in females. Variant X-inactivation Outcomea Number of mutant Strength of Random Skewed To Skewed To wild Escape Males Females alleles variant variantb typec alleled

Biallelic (rare) NA NA NA NA Affected Equally affected as male NA NA NA NA + Affected Equally affected or worse than male Monoallelic Mild to + Affected Less severe or no moderate abnormalities Mild to + Affected Equally affected moderate Mild to + Affected Less or more severe moderate Severe + Fetal lethal Express variant Severe + Fetal lethal Less severe Severe + Fetal lethal Severe or lethal Severe + Fetal lethal Less or more severe X/A + Affected Less severe translocation X/A + Affected More severe translocation aMale phenotype is given; female phenotype is given relative to male. bVariant allele is on the active X. cNormal allele is on the active X. dAllele is also expressed to a small extent from the inactive X.

ɑ-galactosidase may have some of the clinical symptoms influence the direction of skewing. X/autosome translocation seen in affected males, whereas carriers of a variant in a chromosomes are responsible for the rare females afflicted gene encoding another lysosomal enzyme, iduronic sulfa- with Duchenne muscular dystrophy.24 Maternal isodisomy,25 tase, rarely have any clinical symptoms associated with early onset monozygotic twinning (known to promote Hunter syndrome.21 Both enzymes are made in the skewing26,27), and other extreme skewing of X-inactivation28 lysosomes, and can be transported from the lysosomes of have also been responsible for manifesting heterozygotes one cell to those of another cell. The two lysosomal (Table 2). disorders differ because iduronate sulfatase is taken up by Although some skewing may be attributable to abnormal- cells better than the low uptake enzyme, ɑ-galactosidase.22,23 ities of the XIST locus,29 such variants occur only rarely. If This difference in the ability of the lysosome to take up a one XIST allele loses function, than that allele is always on the product is responsible for normal Hunter heterozygotes and active X. Minor loss of function variants of XIST may lead to manifesting Fabry heterozygotes. some skew,29 but few have been reported. Cell selection and random skewing are the most frequent causes of nonrandom OTHER DETERMINANTS OF MANIFESTING X-inactivation. Random skewing frequently occurs because of HETEROZYGOTES events surrounding twinning, and confined placental mosai- One wonders why some heterozygotes express disorders that cism.30 Often skewing is due to the randomness of the do not affect most of the others with the same variant. Some inactivation process, which is stochastic and therefore due to females manifest their X-linked variant because it is over- chance. Ten percent of females are >2 standard deviations expressed; their variant is expressed in more than half their from the mean of 50%.23 cells because of skewing in the proportions of normal and Stochastic skewing that favors cells that inactivate the abnormal cells. Although random inactivation usually means normal WDR45 allele is responsible for neurodegeneration that 34–68% of heterozygous cells are abnormal,12 a few seen in the rare female infants who manifest the X-linked heterozygotes have more than 90% variant cells. Such females pathologic variant (NBIA5), because their brains accumulate manifest the disorder because their wild type allele is not iron. If this disorder is caused by a truncating variant, only expressed sufficiently. These manifesting heterozygotes are mosaic males, or females who are highly skewed favoring the often reported in medical journals because they are affected normal allele, manifest the disease, as all other males and with a disease that usually occurs only in males. In some cases, females with the variant die in utero. Affected females with a chance chromosome translocation or deletion is responsible hypomorphic variants often skew favoring the mutant allele for the skew, as such abnormal X chromosomes often (Table 1).8

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DEGREE OF CELL SELECTION IS DETERMINED BY infectious agents, but it may make them more susceptible to THE VARIANT autoimmunity. Such disorders are nine times as frequent in The X-linked form of Kabuki syndrome is caused either by females than males and are also increased in Klinefelter XXY point variants or deletions in KDM6A. Females with point males, whereas as Turner females, even those taking variants often have Kabuki syndrome, whereas those with the estrogens, have the same risk as XY males. It is now thought larger deletions silence the X carrying the deletion; hence, that the excess manifestations of autoimmune disease in they have less severe manifestations.31 women are due to a complex of issues. Studies in mice show Only a rare heterozygote with a variant in the PLP1 gene that increasing the expression of the X-linked Toll-like has symptoms of the myelin leukodystrophy associated with receptors in susceptible mice increases the expression of the Pelizaeus–Merzbacher syndrome, and she invariably shows autoimmune disorder.36 It has not yet been shown that chance skewing favoring the mutant cells.32 In addition, affected females and Klinefelter males have greater expression during the central nervous system (CNS) development of of their Toll-like receptors than those women and XXY males heterozygotes, the oligodendrocytes with severe PLP1 disease who do not have the disorder. alleles are negatively selected (apoptosis) in favor of wild type Other relevant X-linked genes with potential to influence cells, resulting in skewed X-inactivation that is cell type autoimmunity and that escape X-inactivation include specific.8 CXCR3,37 KDM6A,38 and CXorf21, which has been shown to be more highly expressed in women and Klinefelter males ESCAPE GENES INFLUENCE PHENOTYPE than in normal men.39 In addition, the expression of XIST Another factor that influences the clinical manifestations of from the inactive X in lymphocytes differs significantly from X-linked variants in heterozygotes is the partial expression of that of other cells as the XIST RNA cloud is dispersed, leading genes from the inactive X chromosome.33 In addition to those to poorer Barr body formation.40 No doubt, it is the genes in the pseudoautosomal region that are expressed on interaction of several factors that is responsible for the high both sex chromosomes, more than 100 genes on the human X incidence of autoimmunity associated with having two X chromosome are expressed not only from the active X, but chromosomes. also to some extent from the silent X.34 They are referred to as escape genes. In fact, such genes do not really escape silencing, DIFFERENT DISORDERS FROM THE SAME GENE as they function to some extent, usually producing 10–30% of What is increasingly apparent is that variants in a single gene the level of transcripts made by the homologous allele on the can lead to differently named disorders, because of the specific active X. Yet, this little extra expression of a gene does effect of the variant on production of the gene product. Before influence phenotype. For example, male fetuses with patho- variants were identified, diseases were classified by their logic variants causing orofacial digital syndrome all die in phenotypes and named by the physician who reported the utero, unless they have a second X chromosome (i.e., disease, based on its symptoms. Now, we know that many Klinefelter syndrome); human females survive birth and die different phenotypic disorders may be due to variations in the in their forties, usually from renal failure. However, female same gene; their effect in the heterozygote reflects the severity mice with the same variant outlive males by only several of the variant, which has influenced the naming of the weeks as they die as neonates due to their polycystic kidneys. disorder. Table 1 shows some of these allelic disorders (in The important species difference is that humans, but not bold). Yet, in most cases, no matter the severity of the disease mice, partially express the OFD1 gene from their inactive X.13 in males, the heterozygous female is better off than the This little extra gene activity is responsible for the difference hemizygous male. in age of death of females of the two species. A little extra gene Examples of allelic disorders are the different variants in the product from the inactive X can ameliorate the effects of an IKBKG gene, which can cause incontinentia pigmenti (IP) if X-linked variant (see Table 2). dysfunction is severe, ectodermal dysplasia if dysfunction is The extra product may not be available in every tissue, as moderate, and immunodeficiency 33 if it is mild. When the there are tissue-specific differences in the expression of escape pathologic variant is severe (like IP), females may be the only genes. In several females with a USP9X variant, pigment ones that manifest the disorder, as males die in utero. On the changes along the Blaschko lines and body asymmetry were other hand, when it is moderate, or mild (like immunode- observed, which is probably related to differential escape from ficiency 33), women may completely escape its pathologic X-inactivation between tissues35 and Table 1. effects (Table 1).8 Yet, a little extra activity from the inactive X is not always Another set of allelic disorders is caused by variants in the helpful. It seems that expression of the Toll-like receptors on PRPS1 gene, responsible for syndromes of deafness (missense the inactive X is partly responsible for the impressive sex variant leading to reduced expression), gout (gain of function differences in some cases of autoimmune diseases like Lupus variant), and Charcot–Marie–Tooth disease (more severe and Sjogren disease.36 Toll-like receptors, encoded by the X reduction of expression), depending on the severity of the chromosome, are signaling pattern recognition receptors that specific variant. Again, the heterozygous female always has a are an integral part of innate immunity. The little extra less severe phenotype than the hemizygous male. When the activity may provide females with better protection against male is deaf, the female has high range hearing loss; when he

1172 Volume 22 | Number 7 | July 2020 | GENETICS in MEDICINE MIGEON REVIEW ARTICLE has gout, she has no manifestations. However, when he has selection may eliminate variant cells. Many of these variants optic atrophy and neuropathies, she has much milder affect intellectual ability. Females usually manifest their X- manifestations, or none at all (Table 1).8 linked pathologic variants, if both alleles are disease variants, There is a spectrum of allelic disorders caused by different or if males with the same pathogenic variants are lost in variants in the filamin A gene; again females are always less utero. X-inactivation provides an enormous advantage to affected than males with the same deleterious variants, and females with deleterious X-linked variants, most often are the only ones affected with Melnick–Needles syndrome, enabling them to avoid disease manifestations, including because it is lethal in males (Table 1).8 intellectual disability, that affect males. Fortunately, chance There are also allelic disorders caused by different variations skewing that favors mutant alleles is relatively rare (5%) in in the MECP2 gene. Rett syndrome results when the gene has survivors. The female advantage is reflected by the 20% a deletion or substitution variant that decreases its function; greater death rate for males at every stage postimplantation, the loss of function causes a disorder that is usually lethal to until the age of >75 years, when more females die because unborn males, so that generally only females survive to there are fewer male survivors.41 manifest the disease. However, when the same gene is The females susceptible to X-linked diseases are those who duplicated (Lubs X-linked intellectual disability [XLID], have more than one copy of a pathologic variant, or a relevant Table 1), the increased function permits males to survive second variant, or a variant in an essential gene that does not and manifest the disorder, whereas the gene duplication permit males to survive (Table 2). Females are also susceptible provides the normal allele a selective advantage, so that to chance skewing favoring the mutant allele, or the effects of females escape all manifestations, as the duplicated gene is X chromosomal aberrations (i.e., translocations) and mono- always on the inactive X (Table 1).8 zygotic twinning on inducing unfavorable skewing.42 Another impressive example of the effect of allelic disorders The fact that more males are born than females (1.05:1) is on sex differences in expression of the disease are variants in also likely to be attributable to X-inactivation. In this case, the USP9X gene (Table 1).8,35 As point variants leading to preimplantation females are lost because of their greater truncation are lethal for the male fetus, the manifestations are dosage sensitivity in maintaining an active X.11 But if XX confined to females. On the other hand, less severe individuals successfully establish X-inactivation while in nontruncated variants in the same gene cause hippocampal utero, then throughout their lifetime, they will benefit from related mental retardation, hypotonia, and aggression in the cellular mosaicism it produces. males, whereas carrier females have no abnormalities. ACKNOWLEDGEMENTS MANY X-LINKED GENES ARE ASSOCIATED WITH I am grateful to readers Haig Kazazian, Hans Bjornsson, and INTELLECTUAL DEFICIENCY Steven Salzberg in our McKusick-Nathans Department of Genetic The proportion of X-linked variants causing intellectual Medicine for their helpful comments. Thanks also to Cate Kiefe deficits is striking. In addition to the many X-linked variants for her adaptation of Fig. 1 from Current Opinion in Genetics & whose phenotypes include intellectual disability, there are Development 2006;16:254–259, and to its authors, Brunella many disorders that are specifically associated with X-linked Franco and Andrea Ballabio, for permission to use it. intellectual deficiency, both syndromic and nonsyndromic; these are listed in OMIM as XLID followed by a number from 1 to 107. These disorders map from the telomere of the short DISCLOSURE arm to the last band on the long arm of the X. Although the B.R.M. declares no conflicts of interest. role of the gene whose variant leads to the disorder is not always well defined, the genes responsible for X-linked Publisher’s note Springer Nature remains neutral with regard intellectual disability are involved in many pathways. It seems to jurisdictional claims in published maps and institutional that intelligence is the sum total of how all our genes are affiliations. functioning. Malfunctions of genes in many pathways can interfere with intellectual capabilities. Extreme skewing of X- REFERENCES 1. Kessler E, Rivaud M, Vos M, van Veen T. Sex-specific influence on cardiac inactivation is frequently seen with XLID variants that permit structural remodeling and therapy in cardiovascular disease. Biol Sex male survival, and the variant is always found on the inactive Differ. 2019;10:7. X in females; consequently, they have normal intellectual 2. Natri H, Garcia A, Buetow K, Trumble B, Wilson M. The pregnancy pickle: evolved immune compensation due to pregnancy underlies sex function. Apparently, such disease-producing variants are differences in human diseases. Trends Genet. 2019;35:478–488. toxic for expressing cells. 3. Nuzzi R, Scalabrin S, Becco A, Panzica G. 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Duchenne muscular dystrophy Open Access This article is licensed under a Creative Commons (DMD) in a female with an X/autosome translocation: further evidence Attribution 4.0 International License, which permits use, sharing, that the DMD locus is at Xp21. Am J Hum Genet. 1981;33:513–518. adaptation, distribution and reproduction in any medium or format, as long as 25. Quan F, Janas J, Toth-Fejel S, Johnson DB, Wolford JK, Popovich BW. you give appropriate credit to the original author(s) and the source, provide a link Uniparental disomy of the entire X chromosome in a female with to the Creative Commons license, and indicate if changes were made. The Duchenne muscular dystrophy. Am J Hum Genet. 1997;60:160–165. images or other third party material in this article are included in the article’s 26. Burn J, Povey S, Boyd Y, Munro EA, West L, Harper K, et al. 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