Hypertrophic cardiomyopathy (HCM) is mainly associated with myosin, heavy chain 7 (MYH7) and myosin binding protein C, cardiac (MYBPC3) mutations. In order to better explain the clinical and genetic heterogeneity in HCM patients, in this study, we implemented a target-next generation sequencing (NGS) assay. An Ion AmpliSeq™ Custom Panel for the enrichment of 19 genes, of which 9 of these did not encode thick/intermediate and thin myofilament (TTm) proteins and, among them, 3 responsible of HCM phenocopy, was created. Ninety-two DNA samples were analyzed by the Ion Personal Genome Machine: 73 DNA samples (training set), previously genotyped in some of the genes by Sanger sequencing, were used to optimize the NGS strategy, whereas 19 DNA samples (discovery set) allowed the evaluation of NGS performance. In the training set, we identified 72 out of 73 expected mutations and 15 additional mutations: the molecular diagnosis was achieved in one patient with a previously wild-type status and the pre-excitation syndrome was explained in another. In the discovery set, we identified 20 mutations, 5 of which were in genes encoding non-TTm proteins, increasing the diagnostic yield by approximately 20%: a single mutation in genes encoding non-TTm proteins was identified in 2 out of 3 borderline HCM patients, whereas co-occuring mutations in genes encoding TTm and galactosidase alpha (GLA) altered proteins were characterized in a male with HCM and multiorgan dysfunction. Our combined targeted NGS-Sanger sequencing-based strategy allowed the molecular diagnosis of HCM with greater efficiency than using the conventional (Sanger) sequencing alone. Mutant alleles encoding non-TTm proteins may aid in the complete understanding of the genetic and phenotypic heterogeneity of HCM: co-occuring mutations of genes encoding TTm and non-TTm proteins could explain the wide variability of the HCM phenotype, whereas mutations in genes encoding only the non-TTm proteins are identifiable in patients with a milder HCM status.

The identification of women with a high probability of being carriers of pathogenic BRCA mutation is not straightforward and a major improvement would be the availability of markers of mutations that could be directly evaluated in individuals asking for genetic testing. The FMR1 gene testing was recently proposed as a candidate prescreening tool because an association between BRCA pathogenic mutations and FMR1 genotypes with 'low alleles' (CGG repeat number o26) was observed. To confirm this hypothesis, we evaluated the distribution of FMR1 alleles and genotypes between BRCA mutation carriers and non-carriers in a cohort of 147 Italian women, free of cancer or affected by breast and/or ovarian cancer, who were tested for the presence of BRCA mutation in a clinical setting. The distribution of FMR1 CGG repeat numbers in the two groups was similar (lower allele median/mean were 30/27.4 and 30/27.9, respectively; Mann-Whitney test P ¼ 0.997) and no difference in the FMR1 genotype distribution was present (v 2 ¼ 0.503, d.f. ¼ 2, P ¼ 0.78). This result is in contrast with literature data and suggests that FMR1 genetic testing is not a candidate BRCA prescreening tool. European Journal of Human Genetics (2014) 22, 280-282; doi:10.1038/ejhg.2013 published online 25 September 2013 Keywords: FMR1; BRCA; HBOC; mutation screening INTRODUCTIONThe decision to offer testing for BRCA mutations is challenging in many women in whom an inherited predisposition to breast/ovarian cancer is suspected, because of the associated costs, but also for the difficult interpretation of test results when genetic variants of uncertain significance are detected. Although several tools have been developed to help in this decision, their performance is unsatisfactory. 1 A major improvement would be the availability of markers of pathogenic BRCA mutations that could be directly evaluated in individuals candidate to (or asking for) genetic testing.A low ovarian response rate was observed in BRCA1 mutationpositive women with breast cancer undergoing in vitro fertilization, suggesting an association between BRCA1 mutation and occult primary ovarian insufficiency. 2 Impairment of functional ovarian reserve is associated with another genetic trait, the polymorphic CGG repeat of the Fragile X Mental Retardation 1 (FMR1) gene. 3 Female FMR1 premutation carriers (55-200 CGG repeats) are at increased risk of primary ovarian insufficiency (FXPOI). However, an increased risk of ovarian insufficiency was also reported in women with CGG repeat numbers still within the conventional normal range (o55 CGG repeats) but lower (o26 CGG repeats) or higher (35-55 CGG repeats) of the range of CGG repeats associated with normal folliculogenesis (26-34 CGG repeats). [4][5][6] Recently, Weghofer et al 7 have investigated whether BRCA mutations and FMR1 ovarian genotypes are interdependent: in Austrian women carrying a BRCA mutation they observed almost exclusively the presence of genotypes containing at least one FMR1 allele with a CGG repeat number below 26 (so calle...

Laura Mumoli is a postdoctoral fellow with special interest in epilepsy. SUMMARYGenetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty-seven unrelated patients (35 women; mean age AE standard deviation [SD], 24.1 AE 7.7; mean age AE SD at onset, 15.3 AE 2.4) with JME were enrolled. Twenty-three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease-causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME.

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