Severe microcephalyGene: MINPP1
Comment on list classification: There is sufficient evidence to promote this gene to Green status at the next GMS panel update.
To date, at least 16 individuals from 10 unrelated families reported, all with different biallelic variants in MINPP1 (5 truncating, 6 missense). Main clinical characteristics included mild to severe PCH on brain MRI (16/16), moderate to severe DD/ID (16/16), microcephaly (14/16), and seizures (12/16). Supported by some functional data (PMIDs: 33257696; 33168985)
Created: 12 May 2021, 10:15 a.m. | Last Modified: 12 May 2021, 10:15 a.m.
Panel Version: 2.173
8 individuals from 6 unrelated families reported with bi-allelic LOF variants. All presented with almost complete absence of motor and cognitive development, progressive or congenital microcephaly, spastic tetraplegia or dystonia, and vision impairments. For most, the first symptoms included neonatal severe axial hypotonia and epilepsy that started during the first months or years of life. Prenatal symptoms of microcephaly associated with increased thalami echogenicity were detected in one, while the seven other individuals presented with progressive microcephaly. Some exhibited rapidly progressive phenotype and the affected children died in their infancy or middle-childhood. Strikingly, all the affected children had a unique brain MRI showing a mild to severe PCH, fluid-filled posterior fossa, with dilated lateral ventricles. In addition, severe atrophy at the level of the basal ganglia or thalami often associated with typical T2 hypersignal were identified in all the patients MRI.
Supportive functional data showing accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions.
Created: 9 Dec 2020, 7:49 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
gene: MINPP1 was added gene: MINPP1 was added to Severe microcephaly. Sources: Literature,Expert Review Amber Q2_21_rating tags were added to gene: MINPP1. Mode of inheritance for gene: MINPP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MINPP1 were set to 33257696; 33168985 Phenotypes for gene: MINPP1 were set to Pontocerebellar hypoplasia