title: 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.
authors: Laboratorio di Genetica Medica, Ospedali Riuniti, Bergamo, Italy.
authors: M
authors: M
authors: Iascone
authors: R
authors: R
authors: Ciccone
authors: L
authors: L
authors: Galletti
authors: D
authors: D
authors: Marchetti
authors: F
authors: F
authors: Seddio
authors: A R
authors: AR
authors: Lincesso
authors: L
authors: L
authors: Pezzoli
authors: A
authors: A
authors: Vetro
authors: D
authors: D
authors: Barachetti
authors: L
authors: L
authors: Boni
authors: D
authors: D
authors: Federici
authors: A M
authors: AM
authors: Soto
authors: J V
authors: JV
authors: Comas
authors: P
authors: P
authors: Ferrazzi
authors: O
authors: O
authors: Zuffardi
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D055028:Comparative Genomic Hybridization; D014644:Genetic Variation; D015894:Genome, Human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D051881:Receptor, Notch1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D014157:Transcription Factors; C095552:NKX2-5 protein, human; C497761:NOTCH1 protein, human; C097341:helix-loop-helix protein, eHAND