MYCN is convincingly associated with Feingold syndrome type 1 as an autosomal dominant developmental disorder. Based on the supplied evidence, the MYCN–Feingold syndrome type 1 relationship is Strong: multiple independent case reports and case series identify heterozygous MYCN variants or deletions involving MYCN in clinically concordant individuals and families, and the evidence is consistent with MYCN loss of function as the disease mechanism PMID:33442900, PMID:30088856, PMID:35620261, PMID:32925198.
Human genetic evidence includes 11 affected individuals from 6 families with pathogenic or likely pathogenic MYCN variants in one multi-patient study, with several mildly affected relatives recognized only after segregation analysis of the familial MYCN variant PMID:33442900. An additional three-generation pedigree with 5 affected family members carrying a heterozygous MYCN missense variant further supports segregation of MYCN with Feingold syndrome type 1 PMID:32925198. Single-case reports add independent MYCN-positive probands, including a child with severe intellectual disability and a heterozygous MYCN variant and a family in which Feingold syndrome type 1 due to MYCN was recognized in the setting of coexisting GJB2-related hearing loss PMID:35620261, PMID:40695665. Larger 2p deletions encompassing MYCN in 6 individuals, with clinical information for 5, show that haploinsufficiency of the MYCN region produces core Feingold syndrome type 1 features, although contiguous-gene effects likely contribute to additional findings PMID:30088856.
The reported MYCN variant spectrum in Feingold syndrome type 1 includes truncating and missense alleles, consistent with allelic heterogeneity. Variants explicitly reported in affected individuals include c.1117C>T (p.Arg373Ter), c.1180C>T (p.Arg394Cys), c.1177C>T (p.Arg393Cys), c.1171C>T (p.Arg391Cys), and c.1138_1139del (p.Ser380fs) PMID:33442900, PMID:35620261, PMID:32925198, PMID:40695665. The 2021 series explicitly states that Feingold syndrome type 1 is due to loss-of-function MYCN mutations, while the 2p deletion study is concordant with dosage sensitivity of MYCN PMID:33442900, PMID:30088856. Importantly, separate reports of gain-of-function MYCN variants causing a megalencephaly-polydactyly syndrome support an allele-specific mechanism and help distinguish pathogenic MYCN loss-of-function alleles for Feingold syndrome type 1 from non-Feingold MYCN gain-of-function variants PMID:30573562, PMID:37710961.
The Feingold syndrome type 1 phenotype associated with MYCN is clinically recognizable and repeatedly includes microcephaly, short stature, digital anomalies, and gastrointestinal atresia PMID:33442900, PMID:35620261. Across the supplied MYCN reports, additional manifestations include short palpebral fissures, brachymesophalangy or short middle phalanges, hypoplastic or short thumbs, toe syndactyly, facial dysmorphism, learning disability or intellectual disability, and occasional renal, genital, hearing, or radioulnar anomalies, especially in larger deletions involving MYCN PMID:33442900, PMID:30088856, PMID:40695665. One MYCN family expanded the skeletal spectrum to congenital absence of the flexor pollicis longus tendon, illustrating that MYCN-related Feingold syndrome type 1 can include unusual but developmentally coherent limb findings PMID:32925198. MYCN therefore has clear clinical diagnostic utility in patients with the Feingold syndrome type 1 pattern, particularly when microcephaly and digital anomalies co-occur.
Functional evidence directly tied to Feingold syndrome type 1 is limited in the supplied dataset but directionally supportive. The multi-patient study states that Feingold syndrome type 1 is caused by MYCN loss-of-function variants, and the recurrent observation that deletions including MYCN produce core Feingold syndrome type 1 features supports MYCN haploinsufficiency as the central mechanism PMID:33442900, PMID:30088856. Additional MYCN functional studies in other disease contexts demonstrate that MYCN protein activity is dosage sensitive and biologically important in human development, but these studies are indirect for Feingold syndrome type 1 and should not be overinterpreted for variant classification in this syndrome PMID:30573562, PMID:37710961.
Important limitations remain. The supplied dataset does not provide a comprehensive historical tally of all MYCN-positive Feingold syndrome type 1 families, detailed segregation counts for every pedigree, or variant-level functional testing for most Feingold-associated MYCN alleles. Some severe phenotypes in MYCN-positive individuals may be modified by additional molecular diagnoses, as illustrated by one subject with a maternally inherited MYCN variant plus a separate GNAO1 mutation and another family in which hearing loss was explained by GJB2 in addition to MYCN-related Feingold syndrome type 1 PMID:33442900, PMID:40695665. No conflicting evidence was provided in the supplied dataset.
Overall, the supplied evidence supports MYCN as a clinically valid autosomal dominant cause of Feingold syndrome type 1, with recurrent heterozygous MYCN variants and MYCN-containing deletions producing a characteristic developmental phenotype across independent reports and families PMID:33442900, PMID:30088856, PMID:35620261, PMID:32925198. MYCN should be considered a high-value diagnostic gene in individuals with microcephaly, short stature, digital anomalies, and intestinal atresia, while careful phenotype review is needed to separate MYCN loss-of-function Feingold syndrome type 1 from distinct MYCN gain-of-function developmental disorders PMID:30573562, PMID:37710961. Key take-home: MYCN is a strong, clinically actionable autosomal dominant Feingold syndrome type 1 gene, with the weight of evidence favoring loss of function and haploinsufficiency as the relevant disease mechanism.
Gene–Disease AssociationStrongMultiple independent MYCN-positive probands and families, including 11 patients from 6 families, a 5-member three-generation pedigree, and concordant MYCN-containing deletions causing core Feingold syndrome type 1 features. Genetic EvidenceStrongRecurrent heterozygous MYCN variants and segregating familial cases support autosomal dominant disease; additional MYCN region deletions are phenotypically concordant. Functional EvidenceModerateSupplied studies support MYCN loss of function/haploinsufficiency through variant class and deletion data, but direct syndrome-specific functional assays for most Feingold-associated MYCN alleles are limited. |