Genetics of Hearing Loss: Syndromic

Abstract

Hearing loss (HL) is one of the most common birth defects in developed countries and is a diverse pathologic condition with different classifications. One of these is based on the association with other clinical features, defined as syndromic hearing loss (SHL). Determining the cause of the HL in these patients is extremely beneficial as it enables a personalized approach to caring for the individual. Early screening can further aid in optimal rehabilitation for a child's development and growth. The advancement of high-throughput sequencing technology is facilitating rapid and low-cost diagnostics for patients with SHL.

Keywords: Deafness; Genetics; Genome; Hearing loss; Sequencing.

Fig. 1

Different organs are involved in the clinical symptoms of patients with SHL, in addition to the phenotype in the inner ear. The organs affected in each syndrome are indicated. F, female genitals; M, male genitals.

Fig. 2

Schematic representation of the chromosomal location of genes associated with SHL. The genes are color coded according to the syndrome they are associated with. The genes associated with both syndromic and non-syndromic hearing loss are underlined. Adapted from Dror AA, Avraham KB. Hearing impairment: a panoply of genes and functions. Neuron. 2010;68:293–308; with permission.

Fig. 3

Representative pedigrees of families with HL. (A) Recessive inheritance with no previous family history. After biallelic variants were found in the child, the parents were each found to be carriers of the variant, validating the recessive pattern of inheritance. (B) Recessive inheritance with family history. The family represented in the pedigree presented with symptoms of USH1, with five affected individuals. The chromosomal critical region was defined by the use of microsatellite DNA markers, pinpointing the locus to chromosome 15q22. Several years later, CIB2 was found to be the pathogenic variant responsible for this new form of Usher syndrome, USH1J. (C) Dominant inheritance, with an affected individual in three out of four generations, which may be observed for Waardenburg syndrome with a PAX3, SNAI2 or MITF mutation. (D) A family with both SHL and NSHL. Two patients have Usher syndrome type II, with pathogenic variants in the USH2A gene. One patient has NSHL, due to biallelic pathogenic variants in the GJB2 gene. Data from Refs^{, ,}