A Novel Pathogenic Variant in the MITF Gene Segregating with a Unique Spectrum of Ocular Findings in an Extended Iranian Waardenburg Syndrome Kindred

Abstract

Waardenburg syndrome (WS) is a rare genetic disorder characterized by abnormal pigmentation of the hair, skin, and iris as well as sensorineural hearing loss. WS is subdivided into 4 major types (WS1-4), where WS2 is characterized by the absence of dystopia canthorum. This study was launched to investigate clinical and molecular characteristics of WS in an extended Iranian WS2 family. A comprehensive clinical investigation was performed. Peripheral blood samples were collected and genomic DNA was extracted. Affected members of the family were studied for possible mutations within the SOX10, MITF, and SNAI2 genes. Six WS2 individuals affected from a large Iranian WS2 kindred were enrolled. All affected members carried the novel substitution c.877C>T at exon 9 in the MITF gene, which resulted in p.Arg293* at the protein level. None of the healthy members and also of 50 ethnically matched controls had this variant. In addition, a spectrum of unique ocular findings, including nystagmus, chorioretinal degeneration, optic disc hypoplasia, astigmatism, and myopia, was segregated with the mutant allele in the pedigree. Our data provide insight into the genotypic and phenotypic spectrum of WS2 in an Iranian family and could further expand the spectrum of MITF mutations and have implications for genetic counseling on WS in Iran.

Molecular epidemiology of Chinese Han deaf patients with bi-allelic and mono-allelic GJB2 mutations

“…Consistent with previous studies [17], all three probands with STRC homozygous or compound heterozygous deletions have moderate hearing loss (PTAs of 40-50 dB HL). Fourteen of the sixteen other independent mutations identified in this study have been reported to be associated with hearing loss in previous studies, including dominant mutations EYA1 c.1276G > A (p. G426S) [18] and MITF c.877C > T (p. R293*) [19], recessive mutations PCDH15 c.4133C > T (p. T1378I) and c.1453delT (p. S485Rfs*2) [20], USH2A c.10904C > A (p.T3635 N) [21], MYO15A c.8158G > A (p. D2720N) and c.10258_10260delTTC (p.F3420-) [22], CDH23 c.7630 T > G (p. L2544 V) and c.8257G > A (p.A2753T) [20], OTOF c.2122C > T (p.R708*) and c.1194 T > A (p.D398E) [23,24], SLC26A4 c.1174A > T (p. N392Y) and c.1975G > C (p.V659 L) [25], and SMPX c.55A > G (p. N19D) [26]. One novel hemizygous mutation, c.201delT (p.E68Sfs*11) in TIMM8A, was identified in a male proband D211 as a likely pathogenic mutation since similar Based on the new genetic diagnosis, we revisited the clinical aspects of proband D289 and D554.…”

Vitiligo and melanocytic nevi: New findings in Coffin-Siris syndrome associated with ARID1 germline mutation

“…Specifically, since subunits of the SWI/SNF complex associate with the protein product of the microphthalmia transcription factor ( MITF ) gene, 6 described as a master gene for survival of melanocytes and key transcription factor regulating melanin synthesis, mutations in the SWIF genes present in CSS could affect the transcription of melanin. MITF has various isoforms 7 and mutations associated with a range of phenotypes in pigmented cells 7 . Melanocytic isoform M mutations lead to Waardenburg syndrome type 2A, an auditory pigmented syndrome with hearing loss, patchy depigmentation of the skin, and irides 7 .…”

“…MITF has various isoforms 7 and mutations associated with a range of phenotypes in pigmented cells 7 . Melanocytic isoform M mutations lead to Waardenburg syndrome type 2A, an auditory pigmented syndrome with hearing loss, patchy depigmentation of the skin, and irides 7 . In contrast, a dominant-negative mutation causes Tietze syndrome, characterized by congenital deafness and generalized albinoid-like hypopigmentation of the skin, eyes, and hair 7 .…”

“…Melanocytic isoform M mutations lead to Waardenburg syndrome type 2A, an auditory pigmented syndrome with hearing loss, patchy depigmentation of the skin, and irides 7 . In contrast, a dominant-negative mutation causes Tietze syndrome, characterized by congenital deafness and generalized albinoid-like hypopigmentation of the skin, eyes, and hair 7 . However, there are no data that currently point to a distinctive mutation on the MITF that would critically cause its dysfunction.…”

Whole genome genotyping mapped regions on chromosome 2 and 18 in a family segregating Waardenburg syndrome type II

“…Mutations in PAX3 gene is mainly responsible for the clinical features of WS type I and III, whereas mutations in genes MITF, SOX10 and SNAI2 are identified in WS type II. Genetic mutations in EDN3 and EDNRB have been implicated in WS type IV [8], [6], [10], [5], [9], [19]…”