MYCN

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0958279

Submitter: ClinGen

The *MYCN* gene is located on chromosome 2 at 2p24.3 and encodes *MYCN*, a basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factor belonging to the MYC family. *MYCN* plays a critical role during embryonic development, particularly in the developing nervous system, where it regulates neural progenitor proliferation, cell-cycle progression, ribosome biogenesis, metabolism, and neuronal migration. *MYCN* was initially associated with Feingold syndrome, an autosomal dominant disorder caused by *MYCN* loss-of-function variants, characterised by microcephaly, digital anomalies, gastrointestinal atresia, and intellectual disability. More recently, gain-of-function (GoF) variants in *MYCN* have been identified as the cause of a distinct megalencephaly–polydactyly syndrome, which represents a mirror phenotype to Feingold syndrome. This condition is characterised by megalencephaly or macrocephaly, postaxial polydactyly, cortical thickening, abnormal neuronal migration, developmental delay, and congenital anomalies. Nishio et al. (2023, PMID: 37710961) and Kato et al. (2019, PMID: 30573562) independently reported affected individuals with heterozygous *MYCN* missense variants clustering within the N-terminal phosphodegron region, including c.173C>T (p.Thr58Met) and c.179C>T (p.Pro60Leu). Five missense variants that have been reported in 5 probands in 2 publications (PMIDs: 37710961, 30573562) and ClinVar (SCV006277950.1, SCV005391319.1) are included in this curation. *MYCN* protein levels are tightly controlled through phosphorylation-dependent ubiquitin–proteasome degradation, primarily mediated by sequential phosphorylation at Ser62 and Thr58 and recognition by the SCF-FBW7 E3 ubiquitin ligase complex. Functional studies in non-patient cells demonstrated significantly reduced Thr58 phosphorylation and increased *MYCN* stability for both p.Thr58Met and p.Pro60Leu compared with wild-type *MYCN*, while transcriptional activation of canonical *MYCN* targets such as CCND1 and CCND2 was preserved or enhanced. These findings support a gain-of-function disease mechanism driven by prolonged *MYCN* activity rather than increased intrinsic transcriptional potency. Additional clinical support comes from individuals with nearby missense variants affecting the same regulatory region, including p.Pro44Thr and p.Pro60Ser, reported in ClinVar and diagnostic laboratories, with overlapping phenotypes of macrocephaly, developmental delay, and craniofacial anomalies. Although functional data are limited for these variants, their clustering within the degradation-regulatory domain supports a shared pathogenic mechanism. Experimental evidence further supports this gene–disease relationship including biochemical function, expression, animal model, and functional alterations in non-patient cells (PMIDs: 28969385, 24705253, 30573562, 37710961) In summary, there is moderate evidence to support this gene–disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date January 7th 2026 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: ClinGen

The *MYCN* gene was first reported in relation to autosomal dominant Feingold syndrome type 1 in 2005 (van Bokhoven et al., 2005, PMID: 15821734). This syndrome is characterized by digital anomalies (including brachymesophalangy and syndactyly), microcephaly, gastrointestinal atresias (esophageal and/or duodenal), and variable neurodevelopmental differences. Several unique and recurrent heterozygous loss-of-function variants (nonsense, frameshift, splice-site, or whole-gene deletions) have been reported in unrelated individuals with consistent phenotypes. Evidence supporting this gene–disease relationship includes both case-level and experimental data. Pathogenic variants have been described in more than ten affected probands across several publications and are included in this curation (van Bokhoven et al., 2005 PMID: 15821734; Marcelis et al., 2008 PMID: 18470948; Cogent et al., 2011 PMID: 21224895; Tedesco et al., 2021 PMID: 33442900), with most reported variants occurring de novo or showing autosomal dominant segregation in multiple affected family members. Additional clinical evidence exists in the literature.The mechanism of disease is monoallelic loss of function, supported by truncating variants and whole-gene deletions. *MYCN* is a basic helix-loop-helix transcription factor critical for embryonic development, including in the limb mesenchyme, neural tissues, and enteric epithelium. Expression studies in human embryos show strong developmental expression in these relevant tissues. Western blot confirms *MYCN* protein isoforms are expressed in the fetal brain. In vivo experiments in mice and zebrafish further support the role of *MYCN* in embryogenesis. Conditional knockout of *Mycn* in mouse limb mesenchyme causes shortened limbs and downregulation of miR-17~92, a known *MYCN* target. Zebrafish *mycn* morphants exhibit microcephaly and craniofacial hypoplasia, which are rescued by co-injection of wild-type zebrafish *mycn* mRNA (Li et al., 2022 PMID: 36318514). Single-cell RNA-seq revealed a *Mycn*-sensitive epithelial subpopulation with reduced proliferation. Ribosomal profiling and Northern blot analyses demonstrated defective rRNA processing and reduced 40S, 60S, and 80S ribosomes, impairing translation. Suppressed mTOR signaling contributed to the phenotype, which was mimicked by rapamycin and partially rescued by L-leucine or Rheb supplementation, highlighting *MYCN*’s role in ribosome biogenesis and intestinal development. In summary, *MYCN* is definitively associated with autosomal dominant Feingold syndrome type 1. This classification is supported by multiple de novo and segregating loss-of-function variants in affected individuals, functional data from patient cells and animal models, and rescue experiments. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date July 2nd, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0008115

Submitter: G2P