Severe microcephaly

Gene: ATRIP

Green List (high evidence)

Comment on list classification: There are now 3 unrelated probands reported in literature with severe microcephaly, habrouring homozygous variants in ATRIP. Hence, ATRIP can be promoted to Green on this panel.

Created: 27 Oct 2026, 11:27 a.m. | Last Modified: 27 Oct 2026, 11:28 a.m.

Panel Version: 9.48

PMID: 40029331 Duthoo et al., 2025
Study identified homozygous splice ATRIP variants in two patients of independent ancestry with microcephaly, primordial dwarfism, and recurrent infections.
Patient F1Pt: female with severe microcephaly, developmental delay, dysmorphic features, growth retardation, grossly normal skeletal development, and a mild ID. She had recurrent respiratory tract infections. Lab investigations showed lymphopenia and intermittent neutropenia. WES revealed a homozygous c.829+5G>T variant in ATRIP. Based on figure S1, severity of microcephaly was close to -6 SD below mean for OFC.
Second patient, F46.1, was previously reported in PMID: 35568357.

PMID: 35568357 Masih et al., 2022
Report of 87 Indian families with microcephaly.
P F46.1 - 5yo male - presented with microcephaly OFC 38cm (Z score − 9.4), moderate ID/DD, febrile seizures, facial dysmorphism, dry skin, recurrent respiratory tract infections, clubbing of digits, short stature, speech delay. CT was normal. He was diagnosed with Seckel syndrome. Proband harboured a homozygous ATRIP variant: c.829+2T>G. Method: exome seq.

PMID: 23144622 Ogi et al., 2012 - proband described in review by Rebecca Foulger below.

ATRIP is not yet associated with a disease entity in OMIM. ClinGen and G2P only list AD associations with breast cancer susceptibility. Resources accessed 27th Oct 2026.

Created: 27 Oct 2026, 11:26 a.m. | Last Modified: 27 Oct 2026, 11:26 a.m.

Panel Version: 9.45

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Seckel syndrome, MONDO:0019342

Publications

• 23144622
• 35568357
• 40029331

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11thJuly 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Red

Created: 29 Jul 2019, 4:18 p.m. | Last Modified: 29 Jul 2019, 4:18 p.m.

Panel Version: 1.62

In a patient, born of consanguineous Gujarati-Indian parents, with Seckel syndrome (OMIM:210600), Ogi et al. (PMID:23144622, 2012) identified a heterozygous c.2278C-T transition in exon 12 of the ATRIP gene, resulting in an arg760-to-ter (R760X) substitution. The unaffected mother also carried the mutation. The paternal allele carried a splicing defect affecting exon 2 that was likely subject to NMD. The patient had severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism. The clinical and cellular phenotype was similar to that observed in Seckel patients with ATR mutations but the link between the variant and Seckel syndrome has not been established.

Created: 13 Dec 2016, 10:43 a.m.