Severe microcephaly

Gene: DNA2

Green List (high evidence)

ROTHMUND-THOMSON SYNDROME:
PMID: 37055165 Di Lazzaro Filho et al., 2023
OMIM 620819 summary: Study reported 8 children from 7 families with Rothmund-Thomson syndrome and mutation in the DNA2 gene. 6 of the children were Brazilian and 2 were sibs of Swiss/Portuguese ancestry. Clinical findings included severe growth failure, with some individuals showing signs suggestive of growth hormone or combined pituitary hormone deficiency; widespread poikiloderma; cutaneous photosensitivity and bullae; sparse hair, eyebrows, and eyelashes; dystrophic nails; congenital cataracts and other ocular anomalies, including glaucoma, microphthalmia, and corneal opacities, with Peters anomaly and optic atrophy in 1 patient each; craniofacial dysmorphisms, including severe microcephaly; and skeletal anomalies, including osteopenia, platyspondyly, flared and/or irregular metaphyses, and short metacarpals and phalanges.

6/6 patients above age 2 years had short stature of more than 2 SDS below mean (-4.3 to -8.1SDS). Microcephaly was not severe at birth: between -0.3 to -2.3SDS, but progressed in all patients and was more than -3SDS in unrelated patients.
All 7 probands harboured a recurrent DNA2: c.588–2214A>G intronic variant, in addition to other DNA2 variants in trans: 5 individuals had intragenic exon deletions, one harboured missense variant c.143T>C, p.Leu48Pro (not reported in gnomaD), and sibs in Family 7 had a frameshift variant.

PMID: 40693833 Ay et al., 2025
Report of a female Turkish proband with Rothmund-Thomson syndrome and comp het DNA2 variants: deep intronic c.588-2214A>G and missense c.2519 T>C, Leu840Pro (not in gnomAD v4). She presented with hallmark features of the syndrome: short stature, poikiloderma, corneal dystrophy, bilateral cataracts, skin photosensitivity and blistering, hand contractures, dystrophic nails. Parents are non-consanguineous. Microcephaly not reported; her height was 76cm (-6.3SDS) at 4 yo.

This gene is associated with AR Rothmund-Thomson syndrome, type 4, OMIM:620819 in OMIM as of 11th Sept 2026.

Created: 10 Sep 2026, 4:13 p.m. | Last Modified: 11 Sep 2026, 9:05 a.m.

Panel Version: 9.28

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Rothmund-Thomson syndrome, type 4, OMIM:620819; Seckel syndrome 8, OMIM:615807; Rothmund-Thomson syndrome type 4, MONDO:0970950; Seckel syndrome 8, MONDO:0014350

Publications

• 37055165
• 40693833

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

Created: 10 Mar 2022, 1:37 p.m. | Last Modified: 10 Mar 2022, 1:37 p.m.

Panel Version: 2.292

Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - 4 different homozygous variants identified in at least 5 unrelated families with microcephalic primordial dwarfism (PMIDs: 24389050; 31045292)

Created: 6 May 2021, 9:52 a.m. | Last Modified: 6 May 2021, 9:52 a.m.

Panel Version: 2.142

Green List (high evidence)

Three families described with bi-allelic variants in this gene and a primordial dwarfism/Seckel syndrome phenotype.

Created: 4 Sep 2020, 10:21 a.m. | Last Modified: 4 Sep 2020, 10:21 a.m.

Panel Version: 2.20

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Seckel syndrome 8, MIM#615807

Publications

• 24389050
• 31045292

Variants in this GENE are reported as part of current diagnostic practice

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

Comment when marking as ready: Andrew Jackson (the submitter of the original expert list) confirmed that he considers DNA2 as a candidate gene rather than a clinically confirmed gene for Seckel syndrome. There is only 1 reported allele in OMIM for 2 individuals of the same family.

Created: 3 Jan 2017, 1:57 p.m.

In an 18-year-old uncle and 9-year-old niece, both born of consanguineous marriages with features consistent with Seckel syndrome (SCKL8; OMIM: 615807), Shaheen et al. (PMID:24389050, 2014) identified homozygosity for a 1-bp deletion (c.3372+6delC) in intron 20 of the DNA2 gene, predicted to cause truncation of 1 transcript and abnormal splicing of another 2 transcripts. This is the only recorded variant in OMIM.

Created: 3 Jan 2017, 1:55 p.m.

Confirmed DD gene for PRIMORDIAL DWARFISM SECKEL SYNDROME 8 (OMIM:615807).

Created: 3 Jan 2017, 1:53 p.m.