Macrocephaly_Megalencephaly

Gene: MYCN

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Megalencephaly-polydactyly syndrome, MIM# 620748

Green List (high evidence)

Three individuals now reported with gain-of-function missense variants (identical variant in two individuals). Clinical presentation includes megalencephaly, hypoplastic corpus callosum, postaxial polydactyly, intellectual disability and motor delay. Knock-in mouse model showed morphological manifestations in multiple tissues including digits, female reproductive system and kidney.

Created: 5 Oct 2023, 1:33 a.m. | Last Modified: 5 Oct 2023, 1:33 a.m.

Panel Version: 0.132

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder (MONDO:0700092), MYCN-related

Publications

• PMID:37710961

Mode of pathogenicity
Other

Red List (low evidence)

Single report of a de novo missense p.T58M in an individual with a novel megalencephaly syndrome, a Japanese boy with an intellectual disability (ID), distinctive facies, megalencephaly, ventriculomegaly, hypoplastic corpus callosum, postnatal growth retardation, postaxial polydactyly and neuroblastoma.

Biochemical and cell biology experiments revealed that the mutation renders MYCN resistant to proteolysis and may improperly potentiate cortical neuron proliferation. MYCN activity regulates granule neuron proliferation through induction of CCND1 and CCND2, and this syndrome was similar to CCND2 gene abnormalities that impart excessive protein stability cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. This residue is also frequently mutated in c-Myc in Burkitt’s lymphoma (also due to GoF by gene amplification), consistent with its functions in cell proliferation and differentiation.
Sources: Literature

Created: 21 May 2021, 1:47 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorder with megalencephaly

Publications

• 30573562

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments