Severe microcephalyGene: MCM7
Comment on list classification: Currently there are 3 unrelated pedigrees in literature with different biallelic MCM7 variants associated with disease (PMIDs: 33654309; 34059554). Although there is some functional data in support of variant-level deleteriousness or gene-level pathogenicity, the clinical gestalt is very different between the 3 families.
As no clear phenotype correlations can be made at this time, rating as Amber in anticipation of further cases (2/3 presented severe microcephaly).
Created: 1 Jun 2021, 2:17 p.m. | Last Modified: 1 Jun 2021, 2:17 p.m.
Panel Version: 2.195
MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. Currently, MCM7 is not associated with any phenotype in OMIM or G2P.
- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.
- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Created: 1 Jun 2021, 2:04 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Meier-Gorlin syndrome; Microcephaly; Intellectual disability
Gene: mcm7 has been classified as Amber List (Moderate Evidence).
gene: MCM7 was added gene: MCM7 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MCM7 were set to 33654309; 34059554 Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability Review for gene: MCM7 was set to AMBER