Severe microcephaly

Gene: GPKOW

I don't know

Comment on list classification: Rating Amber as severity of microcephaly is not within the scope of this panel (> -3SD) in all cases. Particularly, in family 1 from PMID: 40221893 where head size increased following birth. This classification could be reviewed if additional cases of severe microcephaly associated with this gene emerge in the future (adding watchlist tag).

PMID: 28612833 - 5 affected males from one family with microcephaly that could be considered within the scope of the panel where biparietal diameter (BPD) is specified (see supplemental).

PMID: 40221893 - 3 affected males from 2 families: F1, in individual 1 HC was −2.4 SD at birth, changing to −1.3 SD at a later examination at 7 weeks, while individual 2 had a HC −3.47 SD at birth and −2.22 SD at 3 months; in F2, individual 3 had HC −3.47 SD at 33-weeks when the pregnancy was terminated. Heterozygous female carriers in F2 also had severe microcephaly, including the mother and sister of individual 3.

Created: 1 Aug 2025, 9:29 a.m. | Last Modified: 1 Aug 2025, 9:29 a.m.

Panel Version: 8.9

Green List (high evidence)

To date, three GPKOW variants have been associated with male-lethal microcephaly with intrauterine growth restriction (PMID: 28612833; 40221893).

Carroll et al 2017 (PMID: 28612833) report a splicing variant (NM_015698.4: c.331+5G>A) in a multigenerational family, with four female carriers, all of those who could be measured have short stature and microcephaly. Male-lethal microcephaly with intrauterine growth restriction was seen in three males within the family and two further male fetuses were terminated after ultrasound diagnosis of intrauterine growth restriction (IUGR). Analysis of patient IV-1 (terminated fetus), showed the presence of a hemizygous NM_015698.4: c.331+5G>A, which had been inherited from his carrier mother.

Two further GPKOW variants were identified by Mok, et al 2025 (PMID: 40221893), in three individuals from two families. These frameshift variants were in the last exon of GPKOW (NM_015698.5: c.1329dupG, p.(Arg441SerfsTer30) and c.1323_1324del, p.(Ser444GlufsTer28)). The male carriers of NM_015698.5: c.1329dupG had IUGR, and other features, but not microcephaly nor lethality. The male carrier of c.1323_1324del had IUGR and microcephaly and was terminated at (33/40). The mothers of these cases had short stature, microcephaly (in one case) and other phenotypic features.

Extensive support from functional studies were also presented in PMID: 28612833; 40221893.

Created: 14 Jul 2025, 8:41 p.m. | Last Modified: 24 Nov 2025, 8:36 p.m.

Panel Version: 8.19

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
syndromic disease, MONDO:0002254

Publications

• 28612833
• 40221893

Green List (high evidence)

The review for this gene will be added to PanelApp at a future date.

Created: 24 Apr 2025, 10:38 a.m. | Last Modified: 24 Apr 2025, 10:38 a.m.

Panel Version: 5.96

I don't know

DDG2P rating in original PAGE list: Probable.

Created: 11 Dec 2018, 9:05 a.m.