Residual risk for additional recessive diseases in consanguineous couples.

PURPOSE: Consanguineous couples are typically counseled based on familial pathogenic variants identified in affected children. The residual risk for additional autosomal recessive (AR) variants, however, remains largely understudied. METHODS: First, we surveyed pedigrees of 1,859 consanguineous families for evidence of more than one AR disease. Second, we mined our database of 1,773 molecularly tested consanguineous families to identify those with more than one AR disease. Finally, we surveyed 88 women from consanguineous unions who have undergone targeted prenatal testing for a familial AR variant and followed the pregnancy outcome (n = 144). RESULTS: We found suggestive evidence of more than one AR disease in 1.94% of consanguineous pedigrees surveyed. Of 1,773 molecularly characterized consanguineous families, 2.93% had evidence of at least two AR diseases (3.54% for first cousin or closer and 2.72% for second cousin or more distant). Furthermore, we found that in 2.78% of pregnancies negative for the familial variant, the pregnancy outcome was a child with a different AR disease. CONCLUSION: Our results show that when counseling consanguineous couples for a familial AR variant, ~3% residual risk for additional AR variants should be discussed. This suggests that a broader testing strategy in consanguineous couples should be considered.

Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.

Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.

Idiopathic Arterial Calcification of Infancy: Case Report.

Idiopathic arterial calcification of infancy is a rare autosomal recessive disease, characterized by deposition of calcium along the internal elastic membrane of arteries, accompanied by fibrous thickening of the intima which causes luminal narrowing. Here we are reporting a case of idiopathic arterial calcification of infancy in a Saudi female newborn of non-consanguineous pregnant woman who had polyhydramnios. The newborn baby had severe respiratory distress, systemic hypertension and persistent pulmonary hypertension of newborn. She was admitted to Neonatal Intensive Care Unit, where she was ventilated and proper treatment was provided. Molecular genetic testing was positive for mutations of ectonucleotide pyrophosphatase/phosphodiesterase1 gene which is reported in 80% of cases of Idiopathic arterial calcification of infancy. The baby died at about 5 month of age because of myocardial ischemia and cardiorespiratory arrest. Idiopathic Arterial Calcification of Infancy should be considered in any newborn who presented with persistent pulmonary hypertension of newborn, severe systemic hypertension and echogenic vessels on any radiological study. Calcifications of large and medium-sized arteries are important diagnostic finding.