Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses

Long QTc in hypertrophic cardiomyopathy. A consequence of structural myocardial damage or a distinct genetic disease?

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, characterized by the presence of unexplained left ventricular hypertrophy. This condition is often associated with electrocardiographic abnormalities including QTc prolongation occurring in 13% of patients. The main explanation for prolonged QTc in HCM is myocardial hypertrophy and the related structural damage. However, other mechanisms, including long QT syndrome (LQTS) genes mutations, may be involved. In the present study we explored the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM by investigating the potential co-inheritance of pathogenic gene variants associated with LQTS and HCM. For this purpose, starting from a cohort of 150 HCM patients carrying pathogenic variants in sarcomere genes, we selected 25 patients carrying a QTc prolongation unexplained by any other cause. The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. The NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform. We identified pathogenic/likely pathogenic variants in the KCNQ1 in two patients (c.1781G > A, p. Arg594Gln; c.532G > A, p. Ala178Thr) (8%). Variants of uncertain significance were identified in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results are limited by the small number of patients included in the study, they highlight a minor contribution of LQTS genes for QTc prolongation in HCM patients. The screening for ion channel genes mutations may be considered in HCM patients with prolonged QTc unexplained by any other cause. This in-depth molecular diagnosis may contribute to improve risk stratification and treatment planning

Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in italian families with breast/ovarian and pancreatic cancers

The 5-10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10-20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches

Nuove mutazioni del gene SETX in pazienti affetti da atassia con Aprassia Oculomotoria di tipo 2 (AOA2)

L’Atassia con Aprassia oculomotoria di tipo 2 (AOA2) (MIM# 606002) è una patologia autosomica recessiva compresa nel sottogruppo delle ARCAs (atassie cerebellari autosomiche recessive) associate ad aprassia oculomotoria (AOA). Questo sottogruppo di ARCAsw oltre all’AOA2 include: l’Atassia Telangiectasia (AT), l’Atassia Telangiectasia Like Disorder (ATLD) e l’Atassia con Aprassia Oculomotoria di tipo 1 (AOA1). I fenotipi clinici mostrano molte similarità e i geni causativi, rispettivamente SETX, ATM, Mre11, APTX, sono tutti implicati nella riparazione delle rotture del DNA. La neurodegenerazione, come in molte altre malattie da difetto di riparazione, è il segno clinico principale. L’AOA2 ha un’età d’insorgenza tra 10 e 22 anni ed è caratterizzata da atassia cerebellare progressiva, neuropatia sensomotoria periferica, aprassia oculomotoria, strabismo, corea e/o distonia. Gli esami di laboratorio rivelano elevati livelli serici di alfa-fetoproteina e creatin chinasi. Lo studio di un'ampia famiglia pachistana ha permesso di localizzare il gene SETX, mutato nell’AOA2, sul cromosoma 9 in posizione q34. SETX codifica per la senatassina, una proteina di 2677 aa contenente nella porzione C-terminale un domino tipico della superfamiglia I e II delle DNA/RNA elicasi. La presenza del dominio elicasico all’interno della senatassina suggerisce un suo coinvolgimento nel processamento degli acidi nucleici e nella stabilità telomerica. Mutazioni nel gene SETX sono state associate oltre che all’AOA2 anche ad una forma dominante di Sclerosi Laterale Amiotrofica (ALS4), alla Sindrome atassica con tremore ed alla Atassia con neuropatia. In questo studio è stata effettuata la caratterizzazione clinica e molecolare di due famiglie turche e di una famiglia italiana con AOA2. L’analisi molecolare ha permesso l’identificazione di tre nuove mutazioni. I due probandi di origine turca sono risultati omozigoti rispettivamente per le mutazioni c.1971delG (p.L657fs) e c.3431insC (p.P1144fs); il paziente di origine italiana è risultato eterozigote composto per la nuova mutazione c.7625_7625delG (p.L2542fs) e per la c.7240C>T (p.R2414X) già descritta in omozigosi in un paziente francese

Phenotype Expression in a Case of Adult Cystic Fibrosis Caused by an Extremely Rare Compound Heterozygous Genotype (2183AA > G/2789+5G > A)

[No abstract available

A New SMAD4 Splice Site Variant in a Three-Generation Italian Family with Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life