Limb disorders

Gene: NCAPG2

I don't know

Khan AJHG 104:94; 2019

Created: 1 Aug 2019, 5:10 p.m. | Last Modified: 1 Aug 2019, 5:10 p.m.

Panel Version: 1.24

I don't know

Comment on list classification: 2 cases. Zebra fish model does not show limb phenotype.

Created: 18 Aug 2019, 9:53 a.m. | Last Modified: 18 Aug 2019, 9:53 a.m.

Panel Version: 1.58

Associated with Khan-Khan-Katsanis syndrome (#618460) in OMIM.

PMID: 30609410 - Khan et al. 2019 - 2 unrelated cases with homozygous or compound heterozygous variants in NCAPG2.
Family 1 - female with bilateral postaxial polydactyly on the feet, moderate intellectual disability, ocular anomalies, sensorineural hearing impairment, sleep apnea, and a short stature. Hydronephrosiss was also observed although this improved over time. She was found to have compound-heterozygous missense NCAPG2 mutations, c.1825A>G (p.Lys609Glu) and c.2078C>T (p.Thr693Met); three healthy siblings are either wild-type (WT) or heterozygous for the mutations (mut). Also of note was a heterozygous NPHP1 deletion, a common contributor to nephronophthisis.
Family 2 - proband was a twin with multiple congenital anomalies at birth; these included microcephaly, facial dysmorphisms, digit abnormalities (postaxial absent toes and clinodactyly of the 5th finger), ocular phenotypes (Peters anomaly, bilateral glaucoma, and buphthalmos of the left eye), contractures, neonatal hypertonia, and a sacral dimple. A homozygous missense variant was found in the proband c.2548A>C [p.Thr850Pro]. Both parents are heterozygous for this variant.
Functional studies with skin fibroblasts from the proband in family 1, showed abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells. In a ncapg2 zebrafish model, morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants.

Created: 7 Aug 2019, 9:14 a.m. | Last Modified: 7 Aug 2019, 9:21 a.m.

Panel Version: 1.35

Gene suggested for the panel by Andrew Wilkie, Oxford University Hospitals NHS Foundation Trust
Sources: Expert list

Created: 1 Aug 2019, 4:18 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal