MYCN – Feingold syndrome type 1

Feingold syndrome type 1 (FS1) is a rare autosomal dominant disorder characterized by microcephaly, short stature, intestinal atresia, and digital anomalies. Pathogenic heterozygous variants in MYCN underlie FS1 through a loss-of-function mechanism, with full penetrance but variable expressivity in affected individuals (Feingold syndrome type 1).

Genetic evidence for the MYCN–FS1 association includes over 120 described probands in the literature, with a recent clinical case report identifying a de novo missense variant c.1177C>T (p.Arg393Cys) (PMID:35620261). A multi-center series of 11 unrelated patients from six distinct families confirmed autosomal dominant inheritance, reporting both novel and recurrent missense variants (e.g., c.1180C>T (p.Arg394Cys)) segregating with disease (PMID:33442900).

Reported MYCN variant classes in FS1 encompass predominantly missense substitutions and occasional truncating alleles, clustering within key functional domains and frequently arising de novo. Segregation studies have demonstrated co-segregation of pathogenic MYCN alleles with FS1 phenotypes in six multiplex families, supporting penetrant autosomal dominant transmission (PMID:33442900).

Functional concordance is provided by interstitial 2p deletions spanning MYCN in six individuals presenting with core FS1 features, establishing haploinsufficiency as the pathogenic mechanism in FS1 (PMID:30088856). Although specific in vitro assays for individual variants are limited, the consistency of phenotype across deletion and sequence variant carriers reinforces loss-of-function as disease‐causing.

Together, the extensive case series, segregation data, and deletion evidence fulfill ClinGen criteria for a definitive gene‐disease relationship. Molecular testing for MYCN loss-of-function variants is therefore recommended for patients with microcephaly, intestinal atresia, short stature, and digital anomalies.

Key take-home: Heterozygous loss-of-function variants in MYCN cause Feingold syndrome type 1 via haploinsufficiency, guiding precise genetic diagnosis and counseling.

References

• Clinical case reports • 2022 • A new variant of MYCN gene as a cause of Feingold syndrome. PMID:35620261
• American journal of medical genetics. Part A • 2021 • Clinical and molecular characterizations of 11 new patients with type 1 Feingold syndrome: Proposal for selecting diagnostic criteria and further genetic testing in patients with severe phenotype. PMID:33442900
• American journal of medical genetics. Part A • 2018 • Features of Feingold syndrome 1 dominate in subjects with 2p deletions including MYCN. PMID:30088856

Evidence Based Scoring (AI generated)