Severe microcephaly

Gene: COPB2

I don't know

Comment on list classification: There are now two unrelated probands reported with the same homozygous missense COPB2 variant and severe microcephaly. Hence, the gene can be rated Amber.

Created: 9 Oct 2026, 11:17 a.m. | Last Modified: 9 Oct 2026, 11:21 a.m.

Panel Version: 9.35

PMID: 37734708 Shiri et al., 2023
Report of a 8.5 yo female proband, born to consanguineous parents. Patient had global developmental delay, intellectual disability, microcephaly (head circumference 42cm, -8.1 SD), seizures, spasticity, strabismus, and failure to thrive symptoms. The proband did not manifest any skeletal problems. She harboured a homozygous NM_004766.3:c.760 C>T, p.Arg254Cys variant - same as in the first Native American family reported in PMID: 29036432. Seq method: WES + Sanger. Parents were heterozygous and unaffected.

Of note, sibs in PMID: 29036432 (DiStasio et al., 2017) also had a CNV reported: 16.8 Mb region of absence of heterozygosity (AOH) on chromosome 3q22.1–3q24 (131,374,802–148,170,986; hg19).

COPB2 is associated with AD Osteoporosis, childhood- or juvenile-onset, with developmental delay, OMIM:619884 and AR ?Microcephaly 19, primary, autosomal recessive, OMIM:617800 (OMIM accessed 9th Oct 2026).

Created: 9 Oct 2026, 11:15 a.m. | Last Modified: 9 Oct 2026, 11:30 a.m.

Panel Version: 9.35

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Microcephaly 19, primary, autosomal recessive, OMIM:617800; microcephaly 19, primary, autosomal recessive, MONDO:0054716

Publications

• 29036432
• 37734708

Red List (low evidence)

PMID: 29036432 - DiStasio et al 2017 - report of severe microcephaly (developing to be below -4.0 SD) and severe intellectual disability in the two siblings with a COPB2 homozygous variant.

The siblings were later investigated for low bone mass in PMID: 34450031 - Marom et al 2021 (in which heterozygous variants in COPB2 in 4 other families with probands with osteoporosis and developmental delay were identified, but no microcephaly reported).
Sources: Literature

Created: 15 Sep 2021, 6:12 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly, HP:0000252

Publications

• 29036432