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. 2020 Jan 2;21(1):1.
doi: 10.1186/s12881-019-0942-4.

Post-lingual non-syndromic hearing loss phenotype: a polygenic case with 2 biallelic mutations in MYO15A and MITF

Athar Khalil  1 , Samer Bou Karroum  1 , Rana Barake  2 , Gabriel Dunya  2 , Samer Abou-Rizk  2 , Amina Kamar  1 , Georges Nemer  3   4 , Marc Bassim  5
Affiliations

Post-lingual non-syndromic hearing loss phenotype: a polygenic case with 2 biallelic mutations in MYO15A and MITF

Athar Khalil et al. BMC Med Genet. .

Abstract

Background: Hearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1-5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases.

Methods: In the current study, we reported a polygenic mode of inheritance in an NSHL consanguineous family using exome sequencing technology and we evaluated the possible effect of the detected single nucleotide variants (SNVs) using in silico methods.

Results: Two bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel MITF p. Pro338Leu missense mutation was predicted to change the protein structure and function.

Conclusion: A novel MITF mutation along with a previously described MYO15A mutation segregate with an autosomal recessive non-syndromic HL case with a post-lingual onset. The findings highlight the importance of carrying whole exome sequencing for a comprehensive assessment of HL genetic heterogeneity.

Keywords: Congenital hearing loss; MITF; MYO15A; Non-syndromic hearing loss; Whole exome sequencing.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Family’s phenotype and genotype. The pedigree of the enrolled family, with affected individuals marked in grey. Possible causative variants of the affected sisters and those of the parents are listed
Fig. 2
Fig. 2
Audiograms of the affected probands. The audiograms show mild to severe progressive hearing loss in both ears for both affected individuals (II.5) and (II.6). The audiograms were taken at the time of diagnosis
Fig. 3
Fig. 3
Chromosomal localization of the MITF missense mutation. The NM_198159.2:c.1013C > T variant on chromosome 3 is visualized Using the IGV software. Both parents (I.1 and I.2) carry the heterozygous form (blue and red), whereas both affected daughters carry the homozygous form (red). The amino acids are shown in the lower panel below their corresponding codons, whereas a straight blue line was shown under the nucleotides that correspond to the intronic region
Fig. 4
Fig. 4
Structural Characterization of the P338 residue. The mouse bHLH amino acid sequence (a) used for depicting the crystal structure of MITF bound to DNA showing the position of the corresponding P338 residue (red circle and arrow) is highly identical to the human sequence (b). The position of the proline residue at position 338 (referred to as Pro 237) is to the outside of the interface of the dimerization interface between two molecules of the mouse MITF bHLH domain (c). (adapted from https://www.rcsb.org/structure/4ATI)
Fig. 5
Fig. 5
Protein structure prediction of the novel MITF variant (p.P338L). In silico modeling (a) the effect of the MITF mutation using the DUET software shows a general destabilization of the structure (b). Wild-type and mutant residues are colored in light-green and are also represented as sticks alongside with the surrounding residues which are involved on any type of interactions (a). The magnitude of the fluctuation is represented by thin to thick tube colored blue (low), white (moderate) and red (high) (b)
See this image and copyright information in PMC

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