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Paternal uniparental disomy of chromosome 13 causing homozygous 35delG mutation of the GJB2 gene and hearing loss

Biallelic mutations of the GJB2 gene are responsible for 28–63% of patients with sporadic or autosomal recessive non-syndromic sensorineural hearing loss [Gasparini et al., 1997]. One mutation, 35delG, is the most common variant, accounting for up to 70% of all GJB2 pathologic alleles in Caucasian patients [Green et al., 1999; Gasparini et al., 2000]. Álvarez et al. [2003] screened parents of 115 unrelated Spanish patients with homozygous 35delG mutation and non-syndromic hearing loss, and found aberrant inheritance of the mutation in two families: one with a 15-year-old affected boy, and the other with a 2-year-old affected girl. In both families, the mothers of the patients carried the mutation, but the fathers did not. Genotyping of microsatellite markers flanking the GJB2 gene in the two patients and their parents indicated that bothpatients resulted from maternal uniparental disomy for chromosome 13 (mat UPD13). In the boy,maternal isodisomy (two copies of one of the maternal homologs) was confined to the 13q11-q12 region with maternal heterodisomy (both copies of the maternal homologs) in the rest of the long arm. In the girl, maternal isodisomic segments alternated with maternal heterodisomic segments along 13q, with the segment close to the centromere isodisomic. It was, therefore, deduced that in both patients, non-disjunction of chromosomes 13 leading to UPD13 occurred in maternal meiosis II, with distal recombinational events resulting in heterodisomic segments. Both patients and the father of the girl all had normal chromosomes. In the present study, we screened the parents of 50 unrelated patients with homozygous 35delG mutation, and found a family in which the father was heterozygous for the mutation but the mother was not. The patient in the family, a Hispanic boy, was referred to us at age 4 years. He had bilateral sensorineural hearing loss: severe to profound on the right, and mild on the left. His development was normal, and no other phenotypic abnormalities were noted. His parents were phenotypically normal without hearing impairment. Tests in the boy, including distortion product otoacoustic emissions, transient-evoked otoacoustic emissions, and brainstem auditory-evoked, indicated cochlear lesion. His hearing level has not changed during 4 years of follow up. Now aged 8 years, he uses a hearing aid in the left ear and has developed age-appropriate speech. We studied the patient and his parents for 29 polymorphic microsatellite markers spanning the long arm of chromosome 13. DNA samples were PCR amplified, separated on denaturing polyacrylamide gels, and visualized, as previously described [Liu et al., 2001]. Fifteen of the 29 markers were informative (Fig. 1). Paternal isodisomy was observed in three segments, and paternal heterodisomy was present in two segments. The most proximal 13q12.1-q13 segment that contains the DFNB1 locus was isodisomic. Alternating heterodisomic and isodisomic segments were observed in the rest of the long arm. This indicates that a