Combined linkage analysis and exome sequencing identifies novel genes for familial goiter

Abstract

Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.

Linkage and whole genome sequencing identify a locus on 6q25–26 for formal thought disorder and implicate MEF2A regulation

“…While a putative effects of the latter were dismissed in a follow-up logistic analysis (data not shown), that of familiarity was not corrected for in these analyses. This is to our knowledge the first study on FTD, a key psychopathological trait of schizophrenia and other psychotic conditions, that combines linkage analysis and next generation sequencing in an experimental strategy that has proven successful for Mendelian diseases (Yan et al, 2013;Zhao et al, 2013). The findings of this study lend support to the growing evidence that impaired MEF2A activity may be involved in the etiology of neuropsychiatric disorders, and that genetic variation in the region 6q26-27 is of specific importance for thought disorders and schizophrenia.…”

Genetic linkage analysis in the age of whole-genome sequencing

“…Linkage analysis has many advantages over filtering approaches in terms of limiting the number of genes that have to be analysed; namely, it takes account of phenocopies and reduced penetrance, which are often features of Mendelian traits, and in addition it provides statistical evidence of the involvement of a variant in disease aetiology. Many new disease susceptibility genes have been successfully identified using linkage analysis coupled with WGS, and this strategy has been successfully used to identify the association of rare variants to phenotypic traits such as hearing impairment 10,89 , familial goitres 90 and familial hypertension 91 . In the future, with the reduction in cost of WGS, linkage analysis of WGS data will be widely used.…”

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…Several new disease susceptibility genes have been successfully identified using linkage analysis coupled with WGS, in complex phenotype disorders such as hearing impairment,50 familial goiters,51 and familial hypertension 52…”