title: Genotype-phenotype correlations in MYCN-related Feingold syndrome.
abstract: Feingold syndrome (FS) is the most frequent cause of familial syndromic gastrointestinal atresia and follows autosomal dominant inheritance. FS is caused by germline mutations in or deletions of the MYCN gene. Previously, 12 different heterozygous MYCN mutations and two deletions containing multiple genes including MYCN were described. All these mutations result in haploinsufficiency of both the canonical MYCN protein and the shorter isoform, DeltaMYCN. We report 11 novel mutations including seven mutations in exon 2 that result in a premature termination codon (PTC) in the long MYCN transcript. Moreover, we have identified a PTC in exon 1 that only affects the DeltaMYCN isoform, without a phenotypic effect. This suggests that mutations in only DeltaMYCN do not contribute to the FS. Additionally, we found three novel deletions encompassing MYCN. Together with our previous report we now have a total of four missense mutations in the DNA binding domain, 19 PTCs of which six render the transcript subject to nonsense-mediated decay (NMD), and five larger deletions in a total of 77 patients. We have reviewed the clinical features of these patients, and found that digital anomalies, e.g., brachymesophalangy and toe syndactyly, are the most consistent features, present in 100% and 97% of the patients, respectively. Small head circumference was present in 89% of the cases. Gastrointestinal atresia remains the most important major congenital anomaly (55%), but cardiac and renal anomalies are also frequent. We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. c.marcelis@antrg.umcn.nl
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Frans A
authors.initials: FA
authors.lastname: Hol
authors.forename: Gail E
authors.initials: GE
authors.lastname: Graham
authors.forename: Paul N M A
authors.initials: PN
authors.lastname: Rieu
authors.forename: Richard
authors.initials: R
authors.lastname: Kellermayer
authors.forename: Rowdy P P
authors.initials: RP
authors.lastname: Meijer
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D004065:Digestive System Abnormalities / Q000235:genetics; D005192:Family Health; D005799:Genes, Dominant; D005838:Genotype; D007409:Intestinal Atresia / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010641:Phenotype; D013576:Syndactyly / Q000235:genetics; D013577:Syndrome; D014034:Toes / Q000002:abnormalities
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins