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H syndrome is a rare autosomal recessive disorder with characteristic dermatological findings consisting of hyperpigmentation and hypertrichosis patches mainly located on the inner thighs and multisystemic involvement including hepatosplenomegaly, hearing loss, heart abnormalities and hypogonadism. The aim of this study was to conduct a clinical and genetic investigation in five unrelated Tunisian patients with suspected H syndrome. Hence, genetic analysis of the SLC29A3 gene was performed for four patients with a clinical diagnosis of H syndrome. We identified a novel frame-shift mutation in the SLC29A3 gene in a female patient with a severe clinical presentation. Furthermore, we report two mutations previously described, the p.R363Q mutation in a male patient and the p.P324L mutation in two patients of different age and sex. This paper extends the mutation spectrum of H syndrome by reporting a novel frame-shift mutation, the p.S15Pfs*86 in exon 2 of SLC29A3 gene and emphasizes the relevance of genetic testing for its considerable implications in early diagnosis and clinical management.

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Pediatric cardiomyopathy is a complex disease with clinical and genetic heterogeneity. Recently, the ALPK3 gene was described as a new hereditary cardiomyopathy gene underlying pediatric cardiomyopathies. Only eight patients carrying mutations in ALPK3 have been reported to date. Here, we report a 3-year-old male patient with both hypertrophic and dilated cardiomyopathy. The patient presented dysmorphic features and skeletal deformities of hands and feet, pectus excavatum, and cleft palate. The genetic investigation was performed by whole-exome sequencing in the patient and his parents. We identified a novel homozygous mutation in ALPK3 (c.1531_1532delAA; p.Lys511Argfs*12). Our work extends the phenotypic spectrum of the ALPK3-associated cardiomyopathy by reporting additional clinical features. This is the first study of a Tunisian patient with mutation in the ALPK3 gene. In conclusion, ALPK3 should be included in the list of genes to be considered in genetic studies for patients affected with pediatric syndromic cardiomyopathy.

Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death.Here we report on a clinical investigation and an extensive genetic assessment of a Tunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify 6 ultra-rare heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV. Overall, our results are highly suggestive for a cumulative effect of several variants as disease causation and to account for a greater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES in the identification of family specific mutations within different cardiac genes pathways.

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia characterized by bidirectional or polymorphic ventricular tachycardia (VT) mostly triggered by exercise or emotional stress. 1 However, many arrhythmias and syncopal episodes occur during "wakeful rest" and normal daily activities. 2 CPVT generally occurs during the first or the second decade of life. 3 Although data on prognosis in CPVT are limited, about 40% of severely affected patients deceased within 10 years of diagnosis. 1,3 More specifically, arrhythmias events and other symptoms such as fainting and dizziness occur between 7 and 11 years. 4 As CPVT is a cardiac

Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.