Monogenic short stature

Gene: DNA2

Red List (low evidence)

Comment on list classification: As noted for Seckel syndrome, Rothmund-Thomson syndrome cases are not in the scope of this panel, because the short stature is syndromic and includes microcephaly.

Created: 11 Sep 2026, 9:09 a.m. | Last Modified: 11 Sep 2026, 9:10 a.m.

Panel Version: 2.9

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: 11 Sep 2026, 9:07 a.m. | Last Modified: 11 Sep 2026, 9:07 a.m.

Panel Version: 2.9

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

Seckel syndrome-related genes are outside the scope of this clinical indication and therefore have been classified as Red on this panel. Seckel syndrome is distinguishable due to marked microcephaly and therefore would be investigated under Severe Microcephaly (R88)

Created: 6 May 2021, 10:33 a.m. | Last Modified: 6 May 2021, 10:33 a.m.

Panel Version: 1.66