Severe microcephaly

Gene: RECQL4

Green List (high evidence)

Comment on list classification: Head circumference was not systematically measured or reported in historical RECQL4 cohorts; therefore, the frequency of microcephaly cannot be determined from those studies. In three more recent reports (2025-2026), 5/6 probands assessed (2 likely related with the same homozygous Turkish founder variant) had microcephaly, with head circumference reported as lower than -3 SD. Hence, this gene can be promoted to Green at the next update.

Created: 5 Oct 2026, 2:28 p.m. | Last Modified: 5 Oct 2026, 2:54 p.m.

Panel Version: 9.34

PMID: 41628607 Genç et al., 2026
Report of 2 Turkish families: 3 sibs with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer), another male proband with a similar presentation and the same homozygous variant, and 2 sibs comp het for c.1663_1664del (p.Ser555GlyfsTer27) and the same p.Gly806_Arg807delinsTer variant - likely Turkish founder variant, all families are from the same region. All individuals had very low height, weight, and head circumference scores for their age.
F1: All 3 affected sibs exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. The severity of microcephaly was -5.2 SD for the proband (III.2). Her younger brother, PIII.6, had head circumference of -3.9 SD, and older sister PIII.2 had head circumference of -2.2 SD at 12yrs old. Parents are first cousins.
F2: Male proband presented with bilateral hearing loss, facial rash, and growth retardation. His head circumference was -4.1 SD below mean at 9 yrs old. Parents are first cousins.
F3: 3yo male with chronic diarrhea and failure to thrive - present since 2 months of age. He developed facial and limb rashes at 9 months old. Alopecia, hyperkeratotic papules, and facial atrophy were also noted at 3 yrs old. Head circumference was noted to be -3.3 SD. Consanguineous parents.

PMID: 40031098 Ho et al., 2025
F1 - Chinese female proband; pregnancy was complicated by IUGR, oligohydramnios, and maternal pre-eclampsia; she had head circumference of 41cm (-3.19 SDS) and height of 59cm (-5.4 SDS) at 11 months old. She also presented with dysplastic nails, borderline dev delay, palmoplantar keratoderma, facial rash, sparse eyebrows and eyelashes, hypo- and hyper-pigmented skin lesions on her legs. She was diagnosed with osteosarcoma at 13 yo. Her younger sister was similarly affected.
WES revealed biallelic RECQL4 variants c.1704+2T>C and p.Arg755Gln.
F2 - Chinese male proband; he presented in infancy with an erythematous rash on sun-exposed areas; skin biopsy was consistent with poikiloderma; he had normal development, sparse eyebrows, normal head circumference and height at 22 months. He was diagnosed with osteosarcoma at 6 years old.
WES detected biallelic RECQL4 variants c.2059-1G>A and p.Glu918*.

PMID: 39324487 Kanai et al., 2025
Two Japanese cases with a severe phenotype and biallelic RECQL4 variants.
P1 - male fetus with severe structural abnormalities, pregnancy was terminated at 21+2 weeks; he harboured biallelic RECQL4 variants c.1390+1G>C and c.1048_1049del, p.Arg350Glyfs*21 (confirmed in trans by WES).
P2 - female infant with height of 28.5cm (-7.7 SD) and head circumference of 27cm (-4.4 SD) at birth; she had digital and skeletal anomalies, and died just after birth due to respiratory insufficiency. She was biallelic for a RECQL4 deletion of exons 12-18 (trio exome).

PMID: 38021400 Martins et al., 2023
Literature review of Rothmund-Thomson syndrome cases. 49 individuals with RECQL4 variants from 43 families are included. While short stature is noted in 34/43 patients, severity is not stated. Microcephaly is marked as 'not reported'.

PMID: 27247962 Suter et al., 2017
Study analysed 43 patients with suspicion of Rothmund–Thomson syndrome and identified 23 different RECQL4 mutations in 18 individuals. Targeted PCR sequencing of RECQL4 was used.
Clinical details are available for 12 patients with biallelic RECQL4 variants: poikiloderma (9/12), characteristic cutaneous rash (5/12), photosensitivity (2/12), alopecia (4), spare eyebrows/eyelashes (6), teeth abnormalities (hypoplastic teeth, microdontia - 3 patients), linear growth deficiency/microsomia (8), variable skeletal anomalies (9/12), delayed development (4), low birth weight / failure to thrive (5); 2 were diagnosed with cancer, one with osteosarcoma at 2 yo. Microcephaly not mentioned.
Sources: Literature

Created: 11 Sep 2026, 4:02 p.m. | Last Modified: 5 Oct 2026, 2:51 p.m.

Panel Version: 9.34

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369

Publications

• 38021400
• 39324487
• 40031098
• 41628607