Challenges in whole exome sequencing: an example from hereditary deafness

Area of Science:

• Genetics
• Molecular Biology
• Ophthalmology

Background:

• Identifying causative DNA variants in rare Mendelian disorders is challenging due to genetic heterogeneity.
• Traditional methods for finding mutations in families with hearing loss are often difficult.

Purpose of the Study:

• To identify the genetic cause of nonsyndromic hearing loss in a consanguineous family using autozygosity mapping and whole exome sequencing.
• To investigate novel genetic variants associated with autosomal recessive nonsyndromic sensorineural hearing loss.

Main Methods:

• Combined autozygosity mapping and whole exome sequencing in a family with affected children and consanguineous parents.
• Identified and analyzed two novel homozygous missense variants (GIPC3 and ZNF57) within an autozygous region.
• Co-segregation analysis and absence in ethnicity-matched controls confirmed variant pathogenicity.

Main Results:

• Two novel homozygous missense variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same autozygous region.
• The GIPC3 variant co-segregated with the hearing loss phenotype and was absent in controls.
• The GIPC3 variant was confirmed as the causative mutation, despite initial challenges with low read depth during analysis.

Conclusions:

• The nonsyndromic hearing loss in this family is caused by a novel missense mutation in the GIPC3 gene.
• This study underscores the complexities of whole exome data analysis in pinpointing causative variants for Mendelian diseases.
• Biallelic GIPC3 mutations are a known cause of autosomal recessive nonsyndromic sensorineural hearing loss.