Putative Digenic GJB2/MYO7A Inheritance of Hearing Loss Detected in a Patient with 48,XXYY Klinefelter Syndrome

<b><i>Objectives:</i></b> Nonsyndromic hearing loss (NSHL) is the most frequent type of hereditary hearing impairment. Here, we explored the underlying genetic cause of NSHL in a three-generation family using whole-exome sequencing. The proband had concomitant NSHL and rare 48,XXYY Klinefelter syndrome. <b><i>Material and Methods:</i></b> Genomic DNA was extracted from the peripheral blood of the proband and their family members. Sanger sequencing and pedigree verification were performed on the pathogenic variants filtered by whole-exome sequencing. The function of the variants was analyzed using bioinformatics software. <b><i>Results:</i></b> The proband was digenic heterozygous for p.V37I in the <i>GJB2</i> gene and p.L347I in the <i>MYO7A</i> gene. The proband’s mother had normal hearing and did not have any variant. The proband’s father and uncle both had NSHL and were compound for the <i>GJB2</i> p.V37I and <i>MYO7A</i> p.L347I variants, thus indicating a possible <i>GJB2/MYO7A</i> digenic inheritance of NSHL. 48,XXYY Klinefelter syndrome was discovered in the proband after the karyotype analysis, while his parents both had normal karyotypes. <b><i>Conclusions:</i></b> Our findings reported a putative <i>GJB2/MYO7A</i> digenic inheritance form of hearing loss, expanding the genotype and phenotype spectrum of NSHL. In addition, this is the first report of concomitant NSHL and 48,XXYY syndrome.

Use of SNPs from Illumina BovineSNP50K BeadChip v3 for imputation of microsatellite alleles for parentage verification and QTL reporting

The present study aimed to test the possibility of avoiding expensive retesting of the whole parental generation for single nucleotide polymorphisms (SNPs), to provide additional analysis of microsatellites in offspring in the transitional period and to analyse the likelihood of imputation of the International Society for Animal Genetics-recommended microsatellite markers from selected SNPs. The imputation and pedigree verification of 9 520 animals (representing 84 dairy bulls, 285 dairy cows, 3 202 beef bulls and 5 949 beef cows) were analysed by the method using 9 410 SNP haplotypes (incorporating an average of 73 SNPs per haplotype). The imputation method was confirmed to allow the parentage verification of up to 87% of the analysed animals without the need for retesting. The most problematic locus was TGLA53, with only 78% successful imputation. Seven loci (BM2113, ETH225, TGLA227, BM1824, SPS115, TGLA122 and TGLA126) had more than 90% imputing accuracy and success of imputation. The success of imputation also depends on the breed and the call rate of the test results. The highest imputation accuracy was found for the Holstein breed; the other six breeds had over 90% successful imputation rates, four breeds had imputation rates between 85.0 and 89.9%, and ten breeds (rarely bred in the Czech Republic) had imputation rates below 85.0%. A call rate of SNP tests lower than 90% indicates problems with haplotype construction and thus deterioration in the success of imputation. The analysis of a possibility of using all possible information from Illumina BovineSNP50K BeadChip v3 showed 109 SNPs encoding 51 quantitative trait loci markers. Haplotypes were designed for interpretation of the most important markers for diseases, exterior and performance. The most important markers for Holstein breeders were chosen as kappa- (variants A, B and E) and beta-casein (variants A1, A2), Holstein haplotypes affecting fertility (HH1, HH3, and HH4) and loci causing genetic defects, bovine leukocyte adhesion deficiency and deficiency of uridine monophosphate synthetase. The results estimated from bovine bead chips corresponded to the expected distribution of the incidence of these traits in the population and were verified by PCR-RFLP tests.

Three Novel Heterozygous COL4A4 Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

Thin basement membrane nephropathy (TBMN), autosomal dominant Alport syndrome (ADAS), and focal segmental glomerulosclerosis (FSGS) are kidney diseases that differ in clinical diagnosis, treatment, and prognosis. Nevertheless, they may result from the same causative genes. Here, we report 3 COL4A4 heterozygous mutations (p.Gly208Arg, p.Ser513Glufs*2, and p.Met1617Cysfs*39) that lead to 3 different collagen type IV kidney disease phenotypes, manifesting as TBMN, ADAS, and FSGS. Using bioinformatics analyses and pedigree verification, we show that these novel variants are pathogenetic and cosegregate with TBMN, ADAS, and FSGS. Furthermore, we found that the collagen type IV-associated kidney disease phenotypes are heterogeneous, with overlapping pathology and genetic mutations. We propose that COL4A4-associated TBMN, ADAS, and FSGS should be considered as collagen type IV kidney disease subtypes that represent different phases of disease progression.

The COL4A3 and COL4A4 Digenic Mutations in cis Result in Benign Familial Hematuria in a Large Chinese Family

Mutations in the COL4A5 gene result in X-linked Alport syndrome, homozygous or compound heterozygous mutations in COL4A3 or COL4A4 are responsible for autosomal recessive Alport syndrome, and heterozygous mutations in COL4A3 or COL4A4 cause autosomal dominant Alport syndrome or benign familial hematuria. Recently, the existence of a digenic inheritance in Alport syndrome has been demonstrated. We here report heterozygous COL4A3 and COL4A4 digenic mutations in cis responsible for benign familial hematuria. Using bioinformatics analyses and pedigree verification, we showed that COL4A4 c.1471C>T and COL4A3 c.3418 + 1G>T variants in cis are pathogenic and co-segregate with the benign familial hematuria. This result suggests that COL4A3 and COL4A4 digenic mutations in cis mimicking an autosomal dominant inheritance should be considered as a novel inheritance pattern of benign familial hematuria, although the disease-causing mechanism remains unknown.