Deafness, Autosomal Recessive 32, With Or Without Immotile Sperm

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-32 with or without immotile sperm (DFNB32) is caused by homozygous mutation in the CDC14A gene (603504) on chromosome 1p21.

Description

DFNB32 is characterized by prelingual progressive moderate to profound sensorineural deafness. Some affected men are infertile, and semen analysis has shown high percentages of immotile sperm with abnormal morphology (Imtiaz et al., 2018).

Clinical Features

Masmoudi et al. (2003) investigated a large consanguineous Tunisian family segregating congenital profound autosomal recessive nonsyndromic deafness. Audiometric tests showed a greater than 70 dB hearing loss in all affected individuals, who were otherwise healthy, with normal life spans and no dysmorphic or other abnormal findings.

Delmaghani et al. (2016) studied 6 of 8 living affected individuals from a consanguineous Iranian family with deafness. The patients ranged in age from 21 to 69 years, and all had prelingual severe to profound deafness of cochlear origin, as shown by markedly increased detection thresholds in pure-tone audiometry and auditory brainstem responses, and by the absence of transient evoked otoacoustic emissions. Otoscopic examination and tympanometry with acoustic reflex testing did not show evidence of conductive hearing impairment. Examination did not reveal any syndromic features, and severe congenital vestibular function was excluded by normal age of walking onset reported by the patients. The pedigree reported for the Iranian family showed 1 fertile deaf man.

Imtiaz et al. (2018) restudied the Tunisian family with deafness originally described by Masmoudi et al. (2003) (family FT1), as well as 5 consanguineous Pakistani families with deafness (HLRB11, HLAI24, HPK1, PKDF539, and PKSN10) and 2 consanguineous Iranian families with deafness (MORL1 and MORL2). Hearing loss ranged from moderate (families HPK1 and PKSN10), in which affected individuals wore hearing aids for oral communication in everyday life, to severe (family PKDF539), in which affected members were profoundly deaf. In some families (HLRB11, HLAI24, and PKDF539), affected individuals in the first or second decade of life had significant hearing loss but with lower thresholds than older family members. In addition, many individuals reported progressive loss of hearing with age, which was corroborated by their parents. No vestibular problems were reported by affected individuals, and no obvious balance problems were detected using Romberg and tandem gait tests. Deaf men from 5 of the families (HLRB11, HLAI24, HPK1, PKDF539, and MORL1) who were married stated that for many years they had been unable to father children. Semen analysis performed in 5 affected men from 4 of the families revealed sperm counts in 4 men that ranged from normal to low-normal, with immotility observed in 60 to 100% of sperm, and abnormal sperm morphology that ranged from 20 to nearly 100% of sperm. In 1 man (family HLRB11), semen analysis yielded no sperm, but white and red blood cells were observed at levels indicative of infection. However, 2 deaf men from family PKSN10 and 1 deaf man from family MORL2 were biologic fathers, and deaf women from families HLRB11, PKDF539, and PKSN10 had multiple children. The authors noted that other men in the study declined semen assessment, and the fertility status of the 3 deaf men in the original Tunisian family (FT1) was reported as unknown.

Inheritance

The transmission pattern of deafness in the families reported by Masmoudi et al. (2003) and Delmaghani et al. (2016) was consistent with autosomal recessive inheritance.

Mapping

In a large consanguineous Tunisian family segregating autosomal recessive congenital profound nonsyndromic deafness, Masmoudi et al. (2003) excluded linkage to known recessive deafness loci and then performed genomewide screening, which demonstrated linkage to a novel locus, designated DFNB32, on chromosome 1. A maximum 2-point lod score of 4.96 was obtained at D1S21401, and haplotype analysis defined a 16-Mb critical region between D1S2868 and afmb014zb9 on chromosome 1p22.1-p13.3.

In a consanguineous Iranian family with autosomal recessive deafness, Delmaghani et al. (2016) performed SNP array analysis and homozygosity mapping that defined a single 2.8-Mb critical region between rs7537296 and rs950060 at chromosome 1p21.2-p21.1. The authors stated that this locus, designated DFNB105, did not match any previously reported human deafness loci; however, in restudying this family, Imtiaz et al. (2018) stated that the DFNB105 linkage interval was entirely within the meiotic breakpoint boundaries of the DFNB32 locus defined by the Tunisian family (FT1) originally studied by Masmoudi et al. (2003).

Molecular Genetics

In a consanguineous Iranian family with autosomal recessive deafness mapping to chromosome 1p21, Delmaghani et al. (2016) performed whole-exome sequencing and identified homozygosity for a nonsense mutation in the CDC14A gene (R376X; 603504.0001) that segregated fully with disease in the family and was not found in 150 Iranian controls or in public databases. Whole-exome sequencing of 115 unrelated individuals from Maghreb with severe or profound congenital deafness identified a Mauritanian patient with profound deafness who was homozygous for another nonsense mutation in CDC14A (R339X; 603504.0002).

In affected individuals from 8 consanguineous families segregating autosomal recessive deafness, including the Tunisian family originally studied by Masmoudi et al. (2003), Imtiaz et al. (2018) identified homozygosity for mutations in the CDC14A gene (see, e.g., 603504.0001 and 603504.0003-603504.0007). Because deaf men from 5 of the families reported infertility and semen analysis showed high percentages of immotile sperm with abnormal morphology, the authors designated the phenotype 'hearing impairment and infertile male syndrome (HIIMS).'

Exclusion Studies

In a large consanguineous Tunisian family segregating autosomal recessive congenital profound deafness mapping to chromosome 1p22.1-p13.3, Masmoudi et al. (2003) screened for mutations in the COL11A1 gene (120280) and excluded it as a candidate gene.