Whole-exome sequencing identifies a potential TTN mutation in a multiplex family with inguinal hernia.

PURPOSE: Inguinal hernia repair is one of the most common procedures in general surgery. Males are seven times more likely than females to develop a hernia and have a 27 % lifetime 'risk' of inguinal hernia repair. Several studies have demonstrated that a positive family history is an important risk factor for the development of primary inguinal hernia, which indicates that genetic factors may play important roles in the etiology of the disease. So far, the contribution of genetic factors and underlying mechanisms for inguinal hernia remain largely unknown. The aim of this study was to investigate a multiplex Estonian family with inguinal hernia across four generations. METHODS: The whole-exome sequencing was carried out in three affected family members and subsequent mutation screening using Sanger sequencing was performed in ten family members (six affected and four unaffected). RESULTS: Whole-exome sequencing in three affected family members revealed a heterozygous missense mutation c.88880A>C (p.Lys29627Thr; RefSeq NM_001256850.1) in the highly conserved myosin-binding A-band of the TTN gene. Sanger sequencing demonstrated that this mutation cosegregated with the disease in this family and was not present in ethnically matched control subjects. CONCLUSION: We report that missense variant in the A-band of TTN is the strongest candidate mutation for autosomal-dominant inguinal hernia with incomplete penetrance.

ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia.

BACKGROUND: Spinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES). METHODS AND RESULTS: WES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified. CONCLUSION: Our study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied.

A missense mutation in DUSP6 is associated with Class III malocclusion.

Class III malocclusion is a common dentofacial phenotype with a variable prevalence according to ethnic background. The etiology of Class III malocclusion has been attributed mainly to interactions between susceptibility genes and environmental factors during the morphogenesis of the mandible and maxilla. Class III malocclusion shows familial recurrence, and family-based studies support a predominance of an autosomal-dominant mode of inheritance. We performed whole-exome sequencing on five siblings from an Estonian family affected by Class III malocclusion. We identified a rare heterozygous missense mutation, c.545C>T (p.Ser182Phe), in the DUSP6 gene, a likely causal variant. This variant co-segregated with the disease following an autosomal-dominant mode of inheritance with incomplete penetrance. Transcriptional activation of DUSP6 has been presumed to be regulated by FGF/FGFR and MAPK/ERK signaling during fundamental processes at early stages of skeletal development. Several candidate genes within a linkage region on chromosome 12q22-q23--harboring DUSP6--are implicated in the regulation of maxillary or mandibular growth. The current study reinforces that the 12q22-q23 region is biologically relevant to craniofacial development and may be genetically linked to the Class III malocclusion.

Non-syndromic tooth agenesis associated with a nonsense mutation in ectodysplasin-A (EDA).

Mutations in the ectodysplasin-A (EDA) gene have been generally associated with X-linked hypohidrotic ectodermal dysplasia (XLHED). Recently, missense mutations in EDA have been reported to cause familial non-syndromic tooth agenesis. In this study, we report a novel EDA mutation in an Estonian family segregating non-syndromic tooth agenesis with variable expressivity. Affected individuals had no associated defects in other ectodermal organs. Using whole-exome sequencing, we identified a heterozygous nonsense mutation c.874G>T (p.Glu292X) in the TNF homology domain of EDA in all affected female patients. This protein-altering variant arose de novo, and the potentially causative allele was transmitted to affected offspring from the affected mother. We suggest that the dental phenotype variability described in heterozygous female carriers of EDA mutation may occur because of the differential pattern of X-chromosome inactivation, which retains reduced levels of EDA-receptor signaling in tissues involved in tooth morphogenesis. This results in selective tooth agenesis rather than XLHED phenotype. The present study broadens the mutation spectrum for this locus and demonstrates that EDA mutations may result in non-syndromic tooth agenesis in heterozygous females.

Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis.

We analyzed the frequency of single-nucleotide polymorphisms (SNPs) at positions -1053 (rs 2981572), 1380 (rs 2981573), 1462 (rs 2232360), and 3978 (rs 1518108) of the human interleukin-20 (IL-20) gene by tetraprimer ARMS-PCR method. A significant association between patients with psoriasis and the G allele at position -1053 (P<0.05) was established. The pairwise linkage disequilibrium (LD) matrix showed that the nearly complete LD was present within the polymorphisms at positions -1053, 1380, and 1462 of the IL-20 gene. We found that patients with plaque psoriasis had a higher frequency of the HT3 GAA haplotype (P<0.01, OR 2.341, 95% CI: 1.346-4.074) compared to the control group. Likewise, the HT3 GAA haplotype was associated with an increased risk of early-onset psoriasis (P<0.01, OR 2.305, 95% CI: 1.285-4.132), late onset of disease (P<0.01, OR 2.542, 95% CI: 1.266-5.102), familial psoriasis (P<0.02, OR 2.220, 95% CI: 1.249-3.945), and sporadic disease (P<0.01, OR 2.523, 95% CI: 1.390-4.580). Our data indicate that IL-20 gene polymorphisms should have a role in determining susceptibility to plaque-type psoriasis. The possible role of the studied SNPs in the regulation of the expression of IL-20 is unknown yet and needs further studies.