Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the PTPRQ Gene Causing Autosomal Recessive Hearing Loss in a Chinese Family

Abstract

Hearing loss is among the most common congenital sensory impairments. Genetic causes account for more than 50% of the cases of congenital hearing loss. The PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, plays an important role in maintaining the stereocilia structure and function of hair cells. Mutations in the PTPRQ gene have been reported to cause hereditary sensorineural hearing loss. By using next-generation sequencing and Sanger sequencing, we identified a novel compound heterozygous mutation (c.997 G > A and c.6603-3 T > G) of the PTPRQ gene in a Chinese consanguineous family. This is the first report linking these two mutations to recessive hereditary sensorineural hearing loss. These findings contribute to the understanding of the relationship between genotype and hearing phenotype of PTPRQ-related hearing loss, which may be helpful to clinical management and genetic counseling.

Keywords: PTPRQ gene; autosomal recessive inheritance; hearing loss; novel compound heterozygous mutation; targeted next-generation sequencing.

FIGURE 1

Family pedigree of two probands. Probands II-1 and II-2 carry compound heterozygous mutation c.997 G > A (chr12:80862555) and c.6603-3 T > G (chr12:81066945) of PTPRQ. The mother of the probands carries heterozygous mutation c.997 G > A. The father of the probands carries heterozygous mutation c.6603-3 T > G. Probands are marked in black. WT, wild type.

FIGURE 2

Clinical audiology examination of the probands. (A) ASSR of Proband II-1 (left ear): 30, 35, 55, 65, 65, and 70 dBnHL at 0.25, 0.5, 1, 2, 4, and 8 kHz. (B) ASSR of Proband II-1 (right ear): 30, 45, 70, 65, 70, and 70 dBnHL at 0.25, 0.5, 1, 2, 4, and 8 kHz. (C) ASSR of Proband II-2 (left ear): 55, 70, 65, 70, and 60 dBnHL at 0.25, 0.5, 1, 2, and 4 kHz. (D) ASSR of the Proband II-2 (right ear): 45, 60, 60, 65, and 60 dBnHL at 0.25, 0.5, 1, 2, and 4 kHz. The hearing threshold of two probands with a hearing aid is marked in red, and the hearing threshold of two probands without a hearing aid is marked in blue.

FIGURE 3

Genetic sequencing results of the probands and their parents. Mutated sequences of the identified c.997 G > A (A) and c.6603-3 T > G (B) variant. The red arrow indicates the site of the base deletion or substitution.

FIGURE 4

Schematic diagram of PTPRQ mutation. (A) Amino acid coding diagram of mutation c.997 G > A. (B) Schematic diagram of PTPRQ peptide chain truncation caused by mutation c.997 G > A. (C) Schematic diagram of mutation c.6603-3 T > G altering hnRNA splicing.