Severe microcephaly

Gene: NCAPD3

I don't know

Homozygous LOF variant prioritised by exomiser in NHS whole genome sequencing case (unpublished). In a patient where clinical correlation with the few cases previously reported seems reasonably high. Not certain this provides sufficient evidence for a strong/definitive gene-disease association to date (PMID: 28552198) but it is further support in favour. Contact NWGLH for details if required.

Created: 20 Jan 2022, 9:33 a.m. | Last Modified: 20 Jan 2022, 9:33 a.m.

Panel Version: 2.277

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 3 p.m. | Last Modified: 1 Feb 2023, 3 p.m.

Panel Version: 3.5

Comment on list classification: Given the discovery of a third patient in the NHS presenting a phenotype consistent with previous reports and functional studies providing a plausible disease mechanism, this gene should now be promoted to Green at the next GMS panel update to ensure detection of cases.

Created: 6 Apr 2022, 11:47 a.m. | Last Modified: 6 Apr 2022, 11:47 a.m.

Panel Version: 2.299

Comment on list classification: Additional cases, as well as a more significant pattern of microcephaly, are required before inclusion of NCAPD3 on a diagnostic panel.

Created: 31 Jul 2020, 3:53 p.m. | Last Modified: 31 Jul 2020, 3:53 p.m.

Panel Version: 2.15

Associated with Microcephaly 22 in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - Two unrelated cases. Compound heterozygous variants ([c.1783_1784delG, p.Val595Serfs*34];[c.382+14A>G, p.Ser129Metfs*1]) were detected in a 6-years-5-month-old male with microcephaly (OFC -5.4 SD). The second patient (aged 6-years-11-months-old) was less severely microcephalic (OFC -2.7 SD) but additionally had moderate developmental delay, seizures and lower limb hypertonia, and also harboured a homozygous missense variant in NCAPD3 (c.3458T>G, p.Glu1153Ala).

Functional studies indicated that both variants disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity. Biallelic variants in other genes encoding subunits of the two condensin complexes result in a similar phenotype.
Sources: Literature

Created: 31 Jul 2020, 3:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Microcephaly 22, primary, autosomal recessive, 617984

Publications

• 27737959