Frequency and origin of the c.2090T>G p.(Leu697Trp) MYO3A variant associated with autosomal dominant hearing loss

Abstract

We recently described a novel missense variant [c.2090T>G:p.(Leu697Trp)] in the MYO3A gene, found in two Brazilian families with late-onset autosomal dominant nonsyndromic hearing loss (ADNSHL). Since then, with the objective of evaluating its contribution to ADNSHL in Brazil, the variant was screened in additional 101 pedigrees with probable ADNSHL without conclusive molecular diagnosis. The variant was found in three additional families, explaining 3/101 (~3%) of cases with ADNSHL in our Brazilian pedigree collection. In order to identify the origin of the variant, 21 individuals from the five families were genotyped with a high-density SNP array (~600 K SNPs- Axiom Human Origins; ThermoFisher). The identity by descent (IBD) approach revealed that many pairs of individuals from the different families have a kinship coefficient equivalent to that of second cousins, and all share a minimum haplotype of ~607 kb which includes the c.2090T>G variant suggesting it probably arose in a common ancestor. We inferred that the mutation occurred in a chromosomal segment of European ancestry and the time since the most common ancestor was estimated in 1100 years (CI = 775-1425). This variant was also reported in a Dutch family, which shares a 87,121 bp haplotype with the Brazilian samples, suggesting that Dutch colonists may have brought it to Northeastern Brazil in the 17th century. Therefore, the present study opens new avenues to investigate this variant not only in Brazilians but also in European families with ADNSHL.

Fig. 1. Segregation of MYO3A variant in three pedigrees.

Pedigrees from families 3 to 5 showing individuals whose phenotype correlates with the segregation of the c.2090T>G:p.(Leu697Trp) in MYO3A. Sanger sequencing was performed in individuals with a plus sign (+) and with a minus sign (−). Individuals indicated with a plus sign are heterozygotes with the c.2090T>G:p.(Leu697Trp) variant; individuals indicated with a minus sign do not carry the variant. Asterisks indicate the individuals who were genotyped by SNP arrays. The probands are indicated with an arrow. Massive parallel sequencing was performed with the sample from the proband of Family 3. a Pedigree of family 3. b Pedigree of family 4. c Pedigree of family 5.

Fig. 2. Brazilian map showing the geographical origin of the ancestors of each family.

Brazilian map highlighting the localization of city of the most ancient known ancestor from families 1–5. In light gray, the states of Paraíba (PB) and Minas Gerais (MG) are highlighted. In dark gray, the Northern region and the Mata region of the state of Minas Gerais are indicated. Four of the five ancestors came from the state of Minas Gerais: Family 1-Visconde do Rio Branco; Family 2-Monte Azul; Family 4-Ubá; Family 5-Monte Azul. The only pedigree whose oldest known ancestor came from the Northeastern region of Brazil is also indicated: Family 3-from Piancó, in the state of Paraíba.

Fig. 3. IBD analysis showing relatedness between 210 pairs of individuals from different families.

k0 is the probability of non-sharing identical-by-descent alleles. The dashed lines correspond to the kinship thresholds for Monozygotic twins, Degree 1 (parent–offspring; full siblings); Degree 2 (half siblings; uncle–nephew; grandfather–grandson), and Degree 3 (first cousins).

Fig. 4. Variant origin by local ancestry inference.

Axis Y represent the phased chromosomes carrying the variant c.2090T>G:p.(Leu697Trp) in MYO3A gene. Axis X represents the 30,117 SNPs genotyped on the chromosome 10. The colors, green, blue, and red represent the African, European, and Native American ancestry, respectively. The vertical black lines point to the variant region, delimiting the minimum shared haplotype.