The MLH1 c.2252_2253delAA mutation was\ud found in 11 unrelated families from a restricted area southwest\ud of Turin among 140 families with mutations in the\ud mismatch repair genes. The mutation is located in the highly\ud conserved C-terminal region, responsible for dimerization\ud with the PMS2 protein. Twenty-five tumour tissues from 61\ud individuals with the c.2252_2253delAA mutation were tested\ud for microsatellite instability(MSI) and protein expression.We\ud compared the clinical features of these families versus the rest\ud of our cohort and screened for a founder effect. All but one\ud tumours showed the MSI-high mutator phenotype. Normal,\ud focal and lack of MLH1 staining were observed in 16, 36 and\ud 48 % of tumours, respectively. PMS2 expression was always\ud lost. The mutation co-segregated with Lynch syndrome-related\ud cancers in all informative families. All families but one\ud fulfilled Amsterdam criteria, a frequency higher than in other\ud MLH1 mutants. This was even more evident for AC II (72.7\ud vs. 57.5 %). Moreover, all families had at least one colon\ud cancer diagnosed before 50 years and one case with multiple\ud Lynch syndrome-related tumours. Interestingly, a statistically\ud significant (p = 0.0057) higher frequency of pancreatic\ud tumourswas observed compared to familieswith other MLH1\ud mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype\ud analysis demonstrated a common ancestral origin of the\ud mutation, which originated about 1,550 years ago. The\ud mutation is currently classified as having an uncertain clinical\ud significance. Clinical features, tissue analysis and co-segregation\ud with disease strongly support the hypothesis that the\ud MLH1 c.2252_2253delAA mutation has a pathogenic effec

Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277-1180_1386 þ 2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.

Background Titin truncating variants (TTNtv) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. However, TTN is not yet included in many NGS panels for congenital musculoskeletal anomalies and dysmorphisms, and karyotype or chromosomal microarray analyses are often the only tests performed when prenatal anomalies are identified. Thereby, many cases caused by TTN defects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum. Methods We analyzed an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv. Results We identified recurrent clinical features in antenatal and congenital recessive titinopathies, including fetal akinesia, arthrogryposis, facial dysmorphisms, joint, bone, and heart anomalies resembling complex, syndromic phenotypes. Conclusion We suggest TTN to be carefully evaluated in any diagnostic process involving patients with the mentioned signs. This step will be essential to improve diagnostic performance, expand our knowledge, and optimize prenatal genetic counseling.

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

BackgroundTitin truncating variants (TTNtvs) have been associated with several forms of myopathies and/or cardiomyopathies. In homozygosity or in compound heterozygosity, they cause a wide spectrum of recessive phenotypes with a congenital or childhood onset. Most recessive phenotypes showing a congenital or childhood onset have been described in subjects carrying biallelic TTNtv in specific exons. Often karyotype or chromosomal microarray analyses are the only tests performed when prenatal anomalies are identified. Thereby, many cases caused byTTNdefects might be missed in the diagnostic evaluations. In this study, we aimed to dissect the most severe end of the titinopathies spectrum.MethodsWe performed a retrospective study analysing an international cohort of 93 published and 10 unpublished cases carrying biallelic TTNtv.ResultsWe identified recurrent clinical features showing a significant correlation with the genotype, including fetal akinesia (up to 62%), arthrogryposis (up to 85%), facial dysmorphisms (up to 73%), joint (up to 17%), bone (up to 22%) and heart anomalies (up to 27%) resembling complex, syndromic phenotypes.ConclusionWe suggestTTNto be carefully evaluated in any diagnostic process involving patients with these prenatal signs. This step will be essential to improve diagnostic performance, expand our knowledge and optimise prenatal genetic counselling.