Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients.

Neurofibromatosis type I (NF1) is one of the most common genetic disorders in humans. NF1, a tumor predisposition syndrome, is caused by heterozygous pathogenic variants in the NF1 gene. Molecular genetic testing of NF1 is complex, especially because of the presence of a high number of partial pseudogenes, some of them with a high percentage of sequence identity. In this study, we have analyzed the largest cohort of NF1 Spanish patients (150 unrelated individuals suspected of having NF1 and 53 relatives, making a total of 203 individuals). Mutation analysis of the entire coding region was performed in all unrelated index patients. Additionally, the Multiplex Ligation-dependent Probe Amplification (MLPA) test of the NF1 gene and SPRED1 gene analysis (sequencing and MLPA test) was performed in some of the negative patients for NF1 point mutations. When fulfilling the National Institutes of Health (NIH) criterion for the clinical diagnosis of NF1, the detection rate was 79%. Among the 80 genetically confirmed NF1 probands, we detected 69 different pathogenic variants. Two mutations (3%) were gross deletions of the whole gene, the remaining 78 mutations (97%) were small changes spread among all NF1 exons. Among these 69 different mutations detected, 42 mutations were described elsewhere, and 27 mutations were novel mutations. When segregation was studied, 67% of mutations resulted de novo variants. No genetic mosaicism was detected on patients' parents.

Transient neonatal zinc deficiency due to a new autosomal dominant mutation in gene SLC30A2 (ZnT-2).

Transient neonatal zinc deficiency (TNZD) has a clinical presentation similar to that of acrodermatitis enteropathica but is caused by a low zinc concentration in maternal breast milk. TNZD becomes clinically evident during breastfeeding and is resolved by weaning and the introduction of complementary nutrition. We present a 4-month-old girl with TNZD due to a new autosomal dominant mutation (663delC) in the maternal SLC30A2 gene not previously described in the literature.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.