Deafness, Autosomal Recessive 68

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-68 (DFNB68) is caused by homozygous mutation in the S1PR2 gene (605111) on chromosome 19p13.

Clinical Features

Santos et al. (2006) reported 2 consanguineous Pakistani families with autosomal recessive nonsyndromic congenital sensorineural hearing loss. In a follow-up of one of these families (DEM4154), reported by Santos et al. (2006) to be negative for limb deformities or any other syndromic features, Santos-Cortez et al. (2016) found that 6 of the 7 affected individuals had severe asymmetric lower limb anomalies, including short and/or bent tibiae, bent or absent fibulae, and absent knee joint. Various foot defects included overlapping or missing digits and syndactyly with soft tissue fusion. One patient had only a mild foot deformity with prominence of the midfoot and interdigital crease, and clubbed toes; x-rays of his knees and feet revealed loss of the medial joint space of the right knee, a lytic lesion of the upper end of the right fibula, and a missing right navicular bone that appeared to be fused to the talus. In addition, the hands of all affected individuals showed long fingers and fifth finger camptodactyly, but radiographs were not available. The authors stated that overall, the asymmetric lower limb deformities resembled tibial hemimelia with split-foot malformation. In a second consanguineous Pakistani family (PKDF1400) reported by Santos-Cortez et al. (2016), affected individuals had profound hearing loss across all frequencies, but exhibited no skeletal, immunologic, cardiovascular, or endocrine features.

Mapping

Santos et al. (2006) reported 2 consanguineous Pakistani families with autosomal recessive nonsyndromic sensorineural hearing loss. Genomewide linkage analysis followed by fine mapping identified a locus, termed DFNB68, on chromosome 19p13.2 (maximum multipoint lod scores of 4.8 and 4.6 at markers D19S581 and D19S432-D19S714-D19S252 in the 2 families, respectively). Haplotype analysis identified a 1.4-Mb (1.9-cM) overlapping interval flanked by markers D19S586 and D19S584. The DFNB68 locus is located within the chromosome 19p13.3-p13.2 region, and DFNB15 (601869) and DFNB81 (614129) are mapped to the same region of chromosome 19. Sequence analysis excluded pathogenic mutations in the KEAP1 (606016), CTL2 (606106), and CDKN2D (600927) genes.

In a consanguineous Pakistani family (DEM4154) with congenital profound deafness and lower limb malformations mapping to chromosome 19, previously studied by Santos et al. (2006), Santos-Cortez et al. (2016) obtained a maximum 2-point lod score of 6.4 (theta = 0) for the R108P variant (605111.0001) in the S1PR2 gene on chromosome 19p13. In another consanguineous Pakistani family (PKDF1400) with isolated hearing impairment, they obtained a maximum multipoint lod score of 3.3 on chromosome 19p13.2-p13.12.

Molecular Genetics

In a consanguineous Pakistani family (DEM4154) with congenital profound deafness and severe asymmetric lower limb malformations mapping to chromosome 19, previously studied by Santos et al. (2006), Santos-Cortez et al. (2016) performed exome sequencing and identified a homozygous missense mutation in the S1PR2 gene (R108P; 605111.0001) that segregated with disease in the family and was not found in 720 Pakistani control chromosomes or in the dbSNP or ExAC databases. In another consanguineous Pakistani family (PKDF1400) with isolated hearing impairment mapping to chromosome 19p13, the authors performed whole-exome sequencing and identified a different missense mutation in S1PR2 (Y140C; 605111.0002) that segregated with disease and was not found in Pakistani controls or public databases. Noting that gross limb deformities were not observed in family PKDF1400 or in S1pr2-null mice, Santos-Cortez et al. (2016) suggested that the limb deformities in family DEM4154 were not due to the mutation in S1PR2 but rather to a variant in another gene.

Exclusion Studies

By sequencing the S1PR2 gene in the other Pakistani family (DEM4100) with congenital deafness studied by Santos et al. (2006), Santos-Cortez et al. (2016) did not detect any mutations; however, they identified a putatively pathogenic variant in the ESSRB gene (602167; see DFNB35, 608565).