Severe microcephaly

Gene: UGGT1

I don't know

Comment on list classification: Severe microcephaly was only reported in five patients from four unrelated families. In addition, there is also phenotypic variability observed within the families where patients were reported with severe microcephaly. Hence, this gene should be rated amber with the current evidence.

Created: 30 Sep 2025, 9:51 a.m. | Last Modified: 30 Sep 2025, 9:51 a.m.

Panel Version: 8.14

PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). However, severe secondary microcephaly (postnatal OFC beyond a Z-score < -3) was only reported in five patients from four families.

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Sources: Literature

Created: 30 Sep 2025, 9:48 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
congenital disorder of glycosylation, MONDO:0015286

Publications

• 40267907