Characterisation and Genetic Mapping of a New X Linked Deafness Syndrome

836 J Med Genet 2000;37:836–841

Characterisation and genetic mapping of a new X J Med Genet: first published as 10.1136/jmg.37.11.836 on 1 November 2000. Downloaded from linked deafness syndrome

Donna M Martin, Frank J Probst, Sally A Camper, Elizabeth M Petty

Abstract are currently over 70 known loci for non- Background—Hereditary forms of hear- syndromic deafness, the responsible gene has ing loss are classified as syndromic, when been identified for fewer than half.2 deafness is associated with other clinical X linked deafness accounts for about 5% of all features, or non-syndromic, when deaf- congenital deafness,3 is genetically heterogene- ness occurs without other clinical fea- ous, and is categorised into seven types (DFN1, tures. Many types of syndromic deafness DFN2, DFN3, DFN4, DFN6, DFN7, and have been described, some of which have DFN8), according to age of onset and type of been mapped to specific chromosomal hearing loss (progressive versus non- regions. progressive, conductive versus sensorineural; see Methods—Here we describe a family with OMIM: http://www.ncbi.nlm.nih.gov/Omim progressive sensorineural hearing loss, and http://hgins.uia.ac.be/dnalab/hhh). Of the cognitive impairment, facial dysmor- seven non-syndromic deafness loci (DFNs) phism, and variable other features, trans- originally mapped to the X chromosome, one mitted by apparent X linked recessive (DFN1/TIMM8A or Mohr-Tranebjærg syn- inheritance. Haplotype analysis of PCR drome) has been associated with other clinical products spanning the X chromosome and features and is now considered syndromic. The direct sequencing of candidate genes were other five known deafness loci are classically used to begin characterising the molecu- non-syndromic, some of which map to Xp lar basis of features transmitted in this (DFN4, DFN6), while others (DFN2 and family. Comparison to known syndromes DFN3/POU3F4) map to Xq. The precise involving deafness, mental retardation, location of DFN8 has not yet been disclosed. facial dysmorphism, and other clinical We describe here a family with a previously features was performed by review of pub- unrecognised, apparently X linked form of lished reports and personal discussions. syndromic congenital bilateral sensorineural Results—Genetic mapping places the can- deafness associated with cognitive impairment, didate locus for this syndrome within a 48 facial dysmorphism, and variable involvement cM region on Xq1-21. Candidate genes of other organ systems. There are some X including COL4A5, DIAPH, and POU3F4 linked deafness syndromes associated with

multiple other clinical problems including cog- http://jmg.bmj.com/ were excluded by clinical and molecular 4 analyses. nitive impairment. Similarly, among the mul- Conclusions—The constellation of clinical tiple X linked loci for mental retardation, findings in this family (deafness, cognitive several have deafness as an associated clinical Departments of impairment, facial dysmorphism, vari- feature. However, none of the previously Pediatrics and able renal and genitourinary abnormali- described deafness-mental retardation syn- Communicable dromes exhibit the specific constellation of Diseases, The ties, and late onset pancytopenia), along University of with a shared haplotype on Xq1-21, clinical findings present in this family. Genetic Michigan, Ann Arbor, suggests that this represents a new form of mapping places the region involved for this on September 25, 2021 by guest. Protected copyright. MI 48109, USA syndromic deafness. We discuss our find- syndrome on the long arm of the X chromo- D M Martin ings in comparison to several other syn- some. Review of publications showed no other dromic and non-syndromic deafness loci reports of families with clinical features similar Department of Human to those present in our family. We present the Genetics, The that have been mapped to the X chromo- clinical features in this family, suggest a poten- University of some. Michigan, 4301 MSRB (J Med Genet 2000;37:836–841) tial map location, and discuss a number of pos- III, Ann Arbor, MI sible candidate genes for this novel syndrome. 48109-0638, USA Keywords: deafness; mental retardation; X chromo- F J Probst some; learning disorder S A Camper Methods E M Petty CLINICAL EVALUATION Approximately one in every 1000 infants is Three males ranging from 12 to 54 years of age Department of Internal Medicine, The born with severe to profound hearing loss, and in one kindred were evaluated for a syndrome University of about half of these cases are believed to have a associated with hearing loss at the request of a Michigan, Ann Arbor, genetic basis.1 Roughly 70% of all cases of female relative desiring preconception counsel- MI 48109, USA genetic deafness occur in the absence of other ling. Review of their pedigree was most E M Petty non-auditory anomalies (non-syndromic deaf- consistent with X linked recessive inheritance, Correspondence to: ness), while the remaining 30% have additional as the aVected males, with strikingly similar Dr Petty, [email protected] congenital abnormalities (syndromic deaf- features, spanned three generations and were ness). The presence of additional symptoms related through unaVected mothers (fig 1). No Revised version received and signs often allows physicians to recognise consanguinity was noted, and no other family 6 September 2000 Accepted for publication the particular gene(s) involved even without members, including a son of a presumed obli- 12 September 2000 extensive genetic linkage analysis. While there gate carrier mother, had known hearing loss or

www.jmedgenet.com X linked deafness syndrome 837 J Med Genet: first published as 10.1136/jmg.37.11.836 on 1 November 2000. Downloaded from I Consultand

Obligate carrier

Unaffected

II Affected Patient 1 (54 y) Clinicallly evaluated

III

Patient 2 (31 y)

Patient 3 (12 y) Figure 1 Pedigree of family. Age at initial evaluation and carrier status is shown. Horizontal line above symbols indicates subjects who were clinically evaluated. learning disabilities. The mother of the 31 year included mild to severe cognitive impairment, old man had isolated congenital unilateral cleft telangiectasias, widely spaced, hypoplastic nip- lip. Features in all of the aVected males are ples, umbilical hernias, and dermatoglyphics listed in table 1. Hearing loss in each aVected characterised by a high number of arches. In male was identified in early childhood and cat- addition, the two older men (aged 31 and 54) egorised as bilateral, sensorineural, severe to had microcephaly, short stature, and pancyto- profound. The two older males exhibited non- penia, which were more severe in the 54 year progressive hearing loss, whereas the 12 year old man. The clinical course of the 54 year old old boy experienced progressive hearing loss, man was also complicated by hypothyroidism, increasing from severe to profound over a 10 diagnosed at the age of 16, and splenomegaly, year period, with subsequent cochlear implan- with normal megakaryocytes, slight hypocellu- tation at the age of 15. Computerised tomogra- larity, and erythroid hyperplasia on bone mar- phy of his temporal bone, done before cochlear row examination. The 12 year old boy also had implantation, showed normal anatomy except a cleft soft palate. for underdeveloped, non-pneumatised mastoid Abnormalities of the genitourinary tract cells. He was reported at 8 months post- were present in the 12 year old boy, who exhib- implantation to be able to detect multiple envi- ited congenital bifid scrotum, small unde- http://jmg.bmj.com/ ronmental sounds, with less improvement so scended testicles and phallus, chordee, and far in speech reception. All three males had absence of the vas deferens and epididymis. normal tympanograms, indicating adequate Testicular biopsy performed during surgical middle ear functioning. Obligate carrier fe- chordee repair and orchidopexy showed nor- males exhibited no hearing loss. mal testicular tissue. Abdominal ultrasound at Mild facial dysmorphism, unique to aVected birth was notable for dysplasia of the left males, was also noted, including telecanthus, kidney. Proteinuria was identified at the age of

hypertelorism, epicanthic folds, broad mouth, 11, and he was treated with angiotensin on September 25, 2021 by guest. Protected copyright. and low set ears (fig 2). Additional features converting enzyme inhibitors to prevent hyper- filtration through the right kidney. The 54 year V Table 1 Clinical features of a ected subjects in the pedigree old man had a history of renal insuYciency and Patient 1 Patient 2 Patient 3 intravenous pyelogram at the age of 46 showed (54 y) (29 y) (12 y) small kidneys (right 7 cm, left 8 cm) with Bilateral sensorineural hearing loss + + + smooth renal margins and faint opacification Microcephaly + + − consistent with chronic glomerulonephritis. Telecanthus + + + The 31 year old man showed no haematuria or Epicanthic folds − + + Narrow palpebral fissures + + − proteinuria on repeated urine analyses and had Broad nasal root + + + no genitourinary or renal abnormalities, as Malar hypoplasia + + + shown by normal abdominal ultrasound at the Dental malocclusion + + + Abnormal teeth + + + age of 25. Full lower lip − + + The degree of cognitive impairment varied Micrognathia − + + among aVected subjects. The 54 year old man Low set ears + + + Myopia + + − was sociable, mild mannered, and exhibited Short stature + + − moderate to severe mental retardation with Umbilical hernia + + + limited speech, but responded to gesture com- Widely spaced, hypoplastic nipples + + + Dermatoglyphics, >5 low arches + + + mands, was cooperative, and social. He at- Abnormal distal interphalangeal creases + + + tended a school for the deaf from 5 to 10 years Telangiectasias + + − Decreased cognitive functioning + + + of age and completed third grade. The 31 year Pancytopenia Severe Mild − old was educated in mainstream school starting Karyotype 46,XY 46,XY 46,XY at third grade, graduated from high school, and subsequently attended a technical college. The

www.jmedgenet.com 838 Martin, Probst, Camper, et al J Med Genet: first published as 10.1136/jmg.37.11.836 on 1 November 2000. Downloaded from http://jmg.bmj.com/ on September 25, 2021 by guest. Protected copyright. Figure 2 AVected family members, aged 12 (upper row), 31 (middle row), and 54 (bottom row) years. Note telecanthus, epicanthic folds, hypertelorism, wide nasal root, malar hypoplasia, low set ears, and broad mouth.

12 year old boy exhibited some learning HAPLOTYPE MAPPING disabilities but attended mainstream education DNA from each subject was prepared from classes. peripheral blood leucocytes with Clonetech Ophthalmological evaluations were notable Nucleospin columns (Palo Alto, California). for mild to severe myopia in the two older Thirty eight primer sequences deﬁning 19 loci aVected males. The 54 year old man also for well mapped, highly polymorphic markers underwent left cataract removal and lens spanning the X chromosome were used to implantation. None of the aVected males genotype aVected males in a stepwise fashion exhibited structural ocular malformations. in this kindred.5 Allele sizes were scored Chromosome analysis of a buccal smear visually against one another and a control. from the 12 year old boy performed at birth for PCR for the ﬁrst and last exons of COL4A5 ambiguous genitalia suggested a mosaic karyo- was performed as previously described.6 Prim- type of 46,XY/45,X. Repeat karyotype of ers were designed to amplify two exons of the peripheral blood at 1 week of age showed nor- DIAPH2 gene based on the partial genomic mal 46,XY chromosomes (100 cells exam- sequence of this gene7 to look for gene ined). Prophase analysis (750-850 bands) of deletions (Genbank direct submission by P peripheral blood chromosomes from the 31 Wray, Accession No Z86061, Sanger Centre, year old man showed no visible microdeletions. Hinxton, Cambridgeshire, UK). Chromosomal analyses of peripheral blood and PCR reactions were performed with the bone marrow from the 54 year old man were markers DXS169, DXS26, and 71:21, as also normal. previously described,8 to rule out a deletion

www.jmedgenet.com X linked deafness syndrome 839

Discussion J Med Genet: first published as 10.1136/jmg.37.11.836 on 1 November 2000. Downloaded from All three maternally related aVected males in this pedigree have severe bilateral congenital sensorineural hearing loss, facial dysmorphism, mild to moderate cognitive impairment, umbilical hernias, and abnormal dermatoglyphics. The older two patients also devel- oped pancytopenia that became progressively worse with age. Extensive review of published reports has shown no similar reports to suggest Region of haplotype a specific diagnosis, implying that these people shared among three probably have a previously unreported deaf- DXS1003 (77) affected males ness syndrome. Environmental influences in the intrauterine, perinatal, or childhood period must be considered as possible causes for the DXS1275 (93) features seen in this family. However, there was POU4F3 no history of medication use or exposure to TIMM8A Xq1-21 radiation or teratogens during the pregnancies DXS990 (104) DIAPH2 of the two younger males. Moreover, the three DXS1106 (115) aVected subjects span a range of over 40 years, COL4A5 and environmental influences common to all DXS1072 (126) three would be expected to have influenced DXS1220 (126) their respective sibs too. Indeed, some features in these subjects are most probably the result of DXS1001 (139) additional unrelated medical problems, such as the hypothyroidism in the 54 year old man. The features common to all three subjects (sensorineural hearing loss, short stature, facial dysmorphism, cognitive impairment, and variable other features including late onset pancytopenia, abnormal dermatoglyphics, and microcephaly) are consistent with a previously undescribed syndrome. These features are present in all three aVected males in this family and absent in females. There is no male to male Figure 3 Chromatogram of the X chromosome with key markers shown on the left. Distances of markers in cM from transmission to suggest autosomal dominant the telomeric end of Xp are shown in parentheses. The solid inheritance, although the pedigree size is vertical bar shows the common haplotype among aVected limited. Mitochondrial inheritance cannot be subjects in this family. Chromosomal locations for all genetic definitively excluded, especially given the mul- markers and candidate genes are available at http://jmg.bmj.com/ http://www.ncbi.nlm.nih.gov/genome/guide/HsChrX.shtml. tisystem involvement of clinical findings and variability among aVected subjects. However, there is no strong evidence of lactic acidosis, proximal to the deafness gene, 89 POU3F4. failure to thrive, encephalopathy, neuropathy, PCR primers were designed to amplify the myopathy, seizures, stroke-like episodes, retini- entire coding sequence of (Genbank POU3F4 tis, or renal tubule disease as is commonly seen direct submission by R Deadman, Accession in mitochondrial disease, and there is no No Z82170, Sanger Centre, Hinxton, Cam-

evidence of matrilineal transmission. on September 25, 2021 by guest. Protected copyright. bridgeshire, UK). Products were purified and Transmission of the clinical features in this sequenced at the University of Michigan DNA family is most consistent with X linked inherit- Sequencing Core. ance. We therefore focused our initial mapping eVorts on the X chromosome. PCR analysis of 19 polymorphic markers on the X chromo- Results some5 showed that all three aVected subjects Genetic mapping of the initial 19 markers indi- share a common haplotype that spans a 48 cM cated that the three aVected subjects share a region of the long arm of the X chromosome. common haplotype spanning a 48 cM region of The likelihood that all males would share this Xq1-21 (fig 3). Several deafness loci have pre- common haplotype by chance alone is 1 in 64, viously been mapped to this region, including strongly suggesting that alteration of a gene or DFN1/TIMM8A, DFN2, COL4A5, DIAPH2, genes within Xq1-21 is responsible for the fea- and DFN3/POU3F4. A second round of PCR tures seen in this syndrome. screening was performed to rule out deletions A number of known syndromic and non- and point mutations in DFN3/POU3F4 and syndromic deafness loci have been previously other candidate regions of the X chromosome mapped to this region. DFN3 maps to Xq21 among aVected subjects. This analysis showed and is a non-syndromic form of mixed deafness no deletions or point mutations in or around caused by mutations in or around the POU3F4 POU3F4. No altered PCR products in the gene.10 Microdeletions and a duplication in- COL4A5 or DIAPH2 genes were identified. volving a region 5' of the POU3F4 gene have These reactions showed that both the COL4A5 been identified in subjects with DFN3. These and DIAPH2 genes are grossly intact in subjects also exhibit a characteristic deficiency aVected members of this pedigree. of bone between the basal turn of the cochlea

www.jmedgenet.com 840 Martin, Probst, Camper, et al

and the internal auditory meatus that is evident Several other syndromes with deafness/ J Med Genet: first published as 10.1136/jmg.37.11.836 on 1 November 2000. Downloaded from on high resolution CT scanning.11 This radio- cognitive impairment as associated features logically detectable cochlear anomaly was map to chromosomal regions within Xq1-21 absent in the 12 year old boy. Moreover, PCR and were considered during clinical evaluation analysis of a number of markers in this region of this family. Juberg-Marsidi syndrome, and complete sequencing of the POU3F4 cod- caused by mutations in ATRX, includes mental ing region indicated that the POU3F4 gene and retardation, deafness, and microgenitalia.16 surrounding regions are grossly intact in While these features were present in some aVected subjects in this pedigree.10 aVected members of our family, this diagnosis Alport syndrome, caused by mutations in the would not adequately explain the dysmor- COL4A5 gene on chromosome Xq21-22, was phism observed in aVected males in this family. recently identified in a family with haematuria, So far, we have been unable to find any large sensorineural hearing loss, and additional deletions in several known candidate genes for features including mental impairment and familial deafness that map to Xq1-21 facial dysmorphism.12 Molecular analysis in (POU3F4, COL4A5, and DIAPH2). There- this family showed a contiguous gene deletion fore, we conclude that this syndrome is either that leads to a complete absence of COL4A5 the result of an unusual mutation not previ- and presumably aVects one or more adjacent ously reported in a known gene (thus produc- loci.12 The features seen in patients with Alport ing a novel phenotype) or, more likely, a muta- syndrome in their report were also diVerent tion in an as yet unidentified gene or genes that from those present in our patients. Moreover, are critical for normal hearing and cognition. the two youngest men in our pedigree have no On prophase karyotype analysis, one band cor- haematuria, making a variant of Alport syn- responds to about 5-10 million base pairs or drome less likely. PCR analysis of the COL4A5 five to 50 average sized genes. Thus, any region gene performed on an aVected family member smaller than this would not be visible by stand- of our pedigree showed that the 5' and 3' ends ard Giemsa staining techniques. A number of of COL4A5 are intact in this family. Therefore, contiguous gene deletions have been identified large deletions which include the 5' and 3' ends in this area17 18 raising the possibility that the of COL4A5 do not explain the symptoms seen disorder we describe here represents a new in our patients. Nevertheless, submicroscopic contiguous gene deletion syndrome. This deletions within the coding region or other hypothesis is particularly attractive considering sequence alterations in COL4A5 might have there are a number of mental retardation loci gone undetected by our analysis. that have been mapped to the X chromosome DIAPH1, a human homologue of the but have yet to be identified. The syndrome we Drosophila gene diaphanous, is mutated in non- describe here may be the result of microdele- syndromic deafness DFNA1 (OMIM 124900). tions not detectable by prophase karyotype A second diaphanous homologue, DIAPH2, analysis. Such a microdeletion may involve the maps to Xq22 and has been proposed as a can- DFN2 or DFN3 loci, positioned within the 48 didate for 7 Using primers based on the cM region where our syndrome maps, or one

DFN2. http://jmg.bmj.com/ published genomic sequence of DIAPH2,we or more other genes on Xq1-21. More reﬁned assayed for large deletions in an aVected family genetic analysis of this family or identiﬁcation member in this pedigree and found no altered of other similarly aVected subjects and families PCR products compared to control DNA. will help elucidate the underlying molecular DFN1/Mohr-Tranebjærg (DFN1/MTS) is a basis of this syndrome and may provide critical syndrome of progressive, sensorineural hearing knowledge about the molecular basis of loss that also presents with neurodegenerative hearing loss and cognitive impairment.

symptoms, dystonia, spasticity, and visual on September 25, 2021 by guest. Protected copyright. impairment. /MTS is associated with DFN1 We thank the patients and their families for participating in this mutations in the deafness/dystonia peptide study, Dr David Ginsburg for referring this family for evaluation ( ) gene.13 The type of neurodegen- and for helpful discussions, and Susan S Sheldon for her cyto- TIMM8A genetic expertise. Support for this study came from the Medical erative symptoms and the progressive nature of Genetics Residency Program (DMM), a University of Michigan hearing loss in /MTS were not seen in Rackham Fellowship (FJP), NIH/NICHD 2RO130428 (SAC), DFN1 and K08 CA66613-01 (EMP). our family. Similarly, all three aVected subjects in the pedigree we describe have symptoms and 1 Gorlin R, Toriello H, Cohen M. Hereditary hearing loss and signs not previously characterised in subjects its syndromes. Oxford: Oxford University Press, 1995. with DFN1/MTS.13 Nevertheless, we cannot 2 Steel KP, Bussoli TJ. Deafness genes: expressions of surprise. Trends Genet 1999;15:207-11. rule out possible genetic heterogeneity within 3 Reardon W. Sex linked deafness: Wilde revisited.JMed DFN1 families, and future analysis of this fam- Genet 1990;27:376-9. 4 Lubs H, Chiurazzi P, Arena J, Schwartz C, Tranebjaerg L, ily is necessary to exclude mutations in the Neri G. XLMR genes: update 1998. Am J Med Genet TIMM8A gene. 1999;83:237-47. 5 Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, DFN2, an additional deafness locus that Millasseau P, Marc S, Bernardi G, Lathrop M, Weissen- maps to this region, is associated with congeni- bach J. The 1993-94 Genethon human genetic linkage map. Nat Genet 1994;7:246-339. tal deafness or non-syndromic progressive 6 Renieri A, Bruttini M, Galli L, Zanelli P, Neri T, Rossetti S, postlingual sensorineural hearing loss. Map- Turco A, Heiskari N, Zhou J, Gusmano R, Massella L, 14 Banﬁ G, Scolari F, Sessa A, Rizzoni G, Tryggvason K, Pig- ping originally placed this locus at Xq21-22 natti PF, Savi M, Ballabio A, De Marchi M. X-linked and the addition of another aVected family Alport syndrome: an SSCP-based mutation survey over all 51 exons of the COL4A5 gene. Am J Hum Genet 1996;58: reﬁned the interval to a 9.2 Mb region of 1192-204. Xq21.15 No other associated features have been 7 Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Nonsyndromic deafness DFNA1 associated with reported in DFN2 families, although there may mutation of a human homolog of the Drosophila gene be clinical heterogeneity within this locus. diaphanous. Science 1997;278:1315-18.

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