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| Severe microcephaly v9.34 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) 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 patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. 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; to: 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 |
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| Severe microcephaly v9.33 | RECQL4 |
Ida Ertmanska changed review comment from: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) 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 patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. 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), teet 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; to: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) 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 patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. 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 |
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| Severe microcephaly v9.32 | RECQL4 |
Ida Ertmanska gene: RECQL4 was added gene: RECQL4 was added to Severe microcephaly. Sources: Literature Mode of inheritance for gene: RECQL4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RECQL4 were set to 38021400; 39324487; 40031098; 41628607 Phenotypes for gene: RECQL4 were set to Rothmund-Thomson syndrome, type 2, OMIM:268400; Rothmund-Thomson syndrome type 2, MONDO:0016369 Review for gene: RECQL4 was set to GREEN Added comment: PMID: 41628607 Genç et al., 2026 Report of 4 patients with Rothmund-Thomson syndrome who were homozygous for c.2415_2419del (p.Gly806_Arg807delinsTer) 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 patients exhibited poikiloderma, facial telangiectasia, skin atrophy, growth retardation, microcephaly, and learning difficulties. 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), teet 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 |
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| Severe microcephaly v2.293 | TRIO | Eleanor Williams Tag Q2_21_rating was removed from gene: TRIO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.292 | TRIO | Sarah Leigh commented on gene: TRIO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.291 | TRIO |
Eleanor Williams Source Expert Review Green was added to TRIO. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Severe microcephaly v2.158 | TRIO | Arina Puzriakova Classified gene: TRIO as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.158 | TRIO | Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green status at the next GMS panel update - microcephaly of relevant severity to this panel is observed in at least 12 unrelated families with TRIO variants. Pathogenicity is supported by functional data and animal model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.158 | TRIO | Arina Puzriakova Gene: trio has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.157 | TRIO | Arina Puzriakova Publications for gene: TRIO were set to 26721934; 32109419 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.156 | TRIO | Arina Puzriakova Tag Q2_21_rating tag was added to gene: TRIO. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.156 | TRIO | Arina Puzriakova Phenotypes for gene: TRIO were changed from Mental retardation, autosomal dominant 44, MIM# 617061 to Intellectual developmental disorder, autosomal dominant 44, with microcephaly, OMIM:617061 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Severe microcephaly v2.20 | TRIO |
Zornitza Stark gene: TRIO was added gene: TRIO was added to Severe microcephaly. Sources: Expert list Mode of inheritance for gene: TRIO was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRIO were set to 26721934; 32109419 Phenotypes for gene: TRIO were set to Mental retardation, autosomal dominant 44, MIM# 617061 Review for gene: TRIO was set to GREEN gene: TRIO was marked as current diagnostic Added comment: The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Sources: Expert list |
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| Severe microcephaly v2.20 | SMO |
Zornitza Stark gene: SMO was added gene: SMO was added to Severe microcephaly. Sources: Expert list Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMO were set to 32413283 Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis Review for gene: SMO was set to GREEN gene: SMO was marked as current diagnostic Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Sources: Expert list |
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