X-Linked Diseases: Susceptible Females

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X-Linked Diseases: Susceptible Females 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():,; GENETICS in MEDICINE 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 Volume 22 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 | Number 7 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 July 2020 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 REVIEW ARTICLE 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 REVIEW ARTICLE 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
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