Identification of de novo mutations and rare variants in hypoplastic left heart syndrome

Abstract

Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart-aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well-characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (NKX2-5, NOTCH1, HAND1, FOXC2 and FOXL1) and genome-wide screening by high-resolution array comparative genomic hybridization. In 30 patients, we identified two novel de novo mutations in NOTCH1, 23 rare patients inherited gene variants in NOTCH1, FOXC2 and FOXL1, and 33 rare patients mostly inherited copy-number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a 'valve' disease. This is the first report of de novo mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease.

Rare DNA copy number variants in cardiovascular malformations with extracardiac abnormalities

“…A review of CNVs in relatively large studies of CVMs 13,22,57,58 showed few subjects with larger segmental aneusomies overlapping the 16 structural variants observed in our study. In a study of 60 individuals with CVMs and ECAs, Thienpont et al 13 described one subject with a derivative chromosome 13 with TOF and microcephaly.…”

O-Glucose Trisaccharide Is Present at High but Variable Stoichiometry at Multiple Sites on Mouse Notch1

“…1 and 2, although larger portions of mN1 (e.g. EGF [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] were also analyzed to confirm that utilization of glycosylation sites was not affected by the size of the fragment being analyzed. Modified peptides were identified by neutral loss of the O-glucose saccharides upon low energy CID fragmentation.…”

“…Defects in Notch signaling have been implicated in a number of human diseases, including several forms of cancer, vascular defects such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (4 -6), multiple sclerosis (6), and a number of developmental syndromes (4,(7)(8)(9)(10). The canonical Notch signaling pathway is initiated by the interaction of Notch with its ligand on an apposed cell.…”

Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q

“…signaturegenomics.com) at the time of the conference, before the study by a Clinical Laboratory Improvement Admendmentscertified laboratory ordered by the patient's local primary care physician or geneticist, or in the laboratory of Dr. Orsetta Zuffardi, Department of Medical Genetics, University of Pavia, Italy, as described previously. 28 Samples tested by the Signature Genomics laboratory utilized the custom-designed OS V2.0 platform, a system that uses 135,000 oligonucleotides with approximately 10-kb resolution in distal 11q, thereby providing a readout of individual genes that are deleted in distal 11q.…”