Bilateral congenital or childhood onset cataracts

Gene: COPB1

Green List (high evidence)

Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

All eight paediatric patients reported to date had severe early-onset cataracts (Khalid et al., 2025 (PMID 40396222); Macken et al., 2021 (PMID 33632302).

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.

Created: 7 Aug 2026, 4:51 p.m. | Last Modified: 7 Aug 2026, 4:51 p.m.

Panel Version: 8.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Baralle-Macken syndrome (OMIM #619255, accessed 08/2026)

Publications

• 33632302
• 40396222

I don't know

COPB1 is associated with a relevant phenotype in OMIM (MIM# 619255) and has a 'possible' disease confidence rating for 'COPB1-related severe intellectual disability syndrome with cataracts and variable microcephaly' in Gene2Phenotype.

- PMID: 33632302 (2021) - six individuals from two unrelated families with different homozygous variants in this gene. All affected patients developed cataracts, among other features such as severe ID and variable microcephaly. Some supportive functional data.

Rating Amber, awaiting further cases.
Sources: Literature

Created: 30 Apr 2021, 8:55 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Baralle-Macken syndrome, OMIM:619255; Severe intellectual disability; Cataracts; Variable microcephaly

Publications

• 33632302