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Severe microcephaly v9.52 ATRIP Achchuthan Shanmugasundram Phenotypes for gene: ATRIP were changed from Seckel syndrome, MONDO:0019342; Microcephalic primordial dwarfism; Severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism to Seckel syndrome, MONDO:0019342
Severe microcephaly v9.48 ATRIP Ida Ertmanska changed review comment from: Comment on list classification: There are now 3 unrelated probands reported in literature with severe microcephaly, habrouring homozygous splice variants in ATRIP. Hence, ATRIP can be promoted to Green on this panel.; to: 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.
Severe microcephaly v9.48 ATRIP Ida Ertmanska Phenotypes for gene: ATRIP were changed from Microcephalic primordial dwarfism; Severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism to Seckel syndrome, MONDO:0019342; Microcephalic primordial dwarfism; Severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism
Severe microcephaly v9.47 ATRIP Ida Ertmanska Publications for gene: ATRIP were set to 23144622
Severe microcephaly v9.46 ATRIP Ida Ertmanska Tag Q4_26_promote_green tag was added to gene: ATRIP.
Severe microcephaly v9.46 ATRIP Ida Ertmanska Classified gene: ATRIP as Amber List (moderate evidence)
Severe microcephaly v9.46 ATRIP Ida Ertmanska Added comment: Comment on list classification: There are now 3 unrelated probands reported in literature with severe microcephaly, habrouring homozygous splice variants in ATRIP. Hence, ATRIP can be promoted to Green on this panel.
Severe microcephaly v9.46 ATRIP Ida Ertmanska Gene: atrip has been classified as Amber List (Moderate Evidence).
Severe microcephaly v9.45 ATRIP Ida Ertmanska reviewed gene: ATRIP: Rating: GREEN; Mode of pathogenicity: None; Publications: 23144622, 35568357, 40029331; Phenotypes: Seckel syndrome, MONDO:0019342; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.44 FTO Ida Ertmanska changed review comment from: PMID: 37529081 Mayman et al., 2023
Case report: female proband homozygous for FTO c.287G>C, p.Arg96Pro.16 months old at time of report. She had numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function, including severe developmental delay. Fetally detected anomalies included polyhydramnios, IUGR (estimated fetal weight <1%), brain anomalies (poor gyral development, small cerebral hemispheres, and Dandy-Walker spectrum anomaly with incompletely rotated vermis, large foramen of Magendie, large cisterna magna, and hydrocephalus), musculoskeletal anomalies (all long bones <5% mean for gestational age without evidence of fracture, thoracic cage 9% mean for gestational age, and disorganized anterior maxillary tooth buds), and cardiovascular (ventricular septal defect, hypoplastic mitral valve, and aortic arch).

PMID: 26697951 Rohena et al., 2016
Report of a homozygous FTO c.965G>A, p.R322Q variant associated with a lethal malformation syndrome in a consanguineous Yemeni family. The 2 affected sibs (male and female) presented with poor growth, microcephaly (<3rd percentile), and cardiac anomalies. Cranial CT of proband A showed severe ventriculomegaly and cerebral atrophy. He also had profound GDD, craniosynostosis, bilateral cataracts, cryptorchidism, micrognathia, and other annomalies.
Proband B, his younger sister, had dysmorphic facial features, clinodactyly, mild clubfeet, and truncal hypotonia with mild spasticity. Both individuals died due to respiratory failure, at 6 and 2.5 years old.
Exome seq also detected a homozygous VUS TRIM37 variant in proband B (TRIM37 is associated with AR growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor - authors note these characteristic features were not present in the siblings).

PMID: 26740239 Çağlayan et al., 2016
Report of a female patient with a homozygous missense mutation in FTO (c.812A>C, p.His271Pro) and a homozygous nonsense mutation p.Arg403X in CETP. No CNVs. Method: WES. CETP is associated with AD Hyperalphalipoproteinemia in OMIM (143470). Parents are second cousins.
Proband presented with microcephaly (head circumference was 41 cm (<2nd percentile) and 9 months old and 47cm (<3rd percentile) at 5 yrs 5 mo), developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia, bilateral hearing loss, and other various phenotypic abnormalities. She had low LDL cholesterol and high HDL cholesterol; diagnosed with CETP-related hyperalphalipoproteinemia.
Western blot analysis demonstrated no changes in patient FTO. Q-PCR analysis revealed slightly decreased levels of FTO expression in patient cells compared to controls.

PMID: 26378117 Daoud et al., 2016
Report of a 21-month-old female with growth retardation and developmental delay, harbouring a homozygous mutation in FTO: p.(Arg316Gln). She presented with distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. Seq method: Targeted NGS panels of 4000+ genes.

PMID: 19559399 Boissel et al. 2009
Report of a consanguineous Palestinian Arab family in which 9 individuals had a severe multiple congenital anomaly syndrome with death by age 3 years. Clinical features dysmorphic facial features, retrognathia, severe failure to thrive in infancy, IUGR (3/9), heart defects (6/9: VSD, AVD, PDA, 4 had hypertrophic cardiomyopathy), severe developmental delay (9/9), microcephaly, lissencephaly, seizures, Dandy-Walker malformation, and other more variable features. Affected individuals were homozygous for FTO:c.947G>A, p.Arg316Gln. Method: autozygosity mapping + targeted analysis of 28 genes on chromosome 16q12.

FTO is associated with AR Growth retardation, developmental delay, facial dysmorphism, OMIM:612938 (OMIM accessed 23rd Oct 2026).
Sources: Literature; to: PMID: 37529081 Mayman et al., 2023
Case report: female proband homozygous for FTO c.287G>C, p.Arg96Pro.16 months old at time of report. She had numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function, including severe developmental delay. Fetally detected anomalies included polyhydramnios, IUGR (estimated fetal weight <1%), brain anomalies (poor gyral development, small cerebral hemispheres, and Dandy-Walker spectrum anomaly with incompletely rotated vermis, large foramen of Magendie, large cisterna magna, and hydrocephalus), musculoskeletal anomalies (all long bones <5% mean for gestational age without evidence of fracture, thoracic cage 9% mean for gestational age, and disorganized anterior maxillary tooth buds), and cardiovascular (ventricular septal defect, hypoplastic mitral valve, and aortic arch). No microcephaly.

PMID: 26697951 Rohena et al., 2016
Report of a homozygous FTO c.965G>A, p.R322Q variant associated with a lethal malformation syndrome in a consanguineous Yemeni family. The 2 affected sibs (male and female) presented with poor growth, microcephaly (<3rd percentile), and cardiac anomalies. Cranial CT of proband A showed severe ventriculomegaly and cerebral atrophy. He also had profound GDD, craniosynostosis, bilateral cataracts, cryptorchidism, micrognathia, and other annomalies.
Proband B, his younger sister, had dysmorphic facial features, clinodactyly, mild clubfeet, and truncal hypotonia with mild spasticity. Both individuals died due to respiratory failure, at 6 and 2.5 years old.
Exome seq also detected a homozygous VUS TRIM37 variant in proband B (TRIM37 is associated with AR growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor - authors note these characteristic features were not present in the siblings).

PMID: 26740239 Çağlayan et al., 2016
Report of a female patient with a homozygous missense mutation in FTO (c.812A>C, p.His271Pro) and a homozygous nonsense mutation p.Arg403X in CETP. No CNVs. Method: WES. CETP is associated with AD Hyperalphalipoproteinemia in OMIM (143470). Parents are second cousins.
Proband presented with microcephaly (head circumference was 41 cm (<2nd percentile) and 9 months old and 47cm (<3rd percentile) at 5 yrs 5 mo), developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia, bilateral hearing loss, and other various phenotypic abnormalities. She had low LDL cholesterol and high HDL cholesterol; diagnosed with CETP-related hyperalphalipoproteinemia.
Western blot analysis demonstrated no changes in patient FTO. Q-PCR analysis revealed slightly decreased levels of FTO expression in patient cells compared to controls.

PMID: 26378117 Daoud et al., 2016
Report of a 21-month-old female with growth retardation and developmental delay, harbouring a homozygous mutation in FTO: p.(Arg316Gln). She presented with distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. Microcephaly was borderline severe (at the 2nd centile). Seq method: Targeted NGS panels of 4000+ genes.

PMID: 19559399 Boissel et al. 2009
Report of a consanguineous Palestinian Arab family in which 9 individuals had a severe multiple congenital anomaly syndrome with death by age 3 years. Clinical features dysmorphic facial features, retrognathia, severe failure to thrive in infancy, IUGR (3/9), heart defects (6/9: VSD, AVD, PDA, 4 had hypertrophic cardiomyopathy), severe developmental delay (9/9), microcephaly, lissencephaly, seizures, Dandy-Walker malformation, and other more variable features. Affected individuals were homozygous for FTO:c.947G>A, p.Arg316Gln. Method: autozygosity mapping + targeted analysis of 28 genes on chromosome 16q12.

FTO is associated with AR Growth retardation, developmental delay, facial dysmorphism, OMIM:612938 (OMIM accessed 23rd Oct 2026).
Sources: Literature
Severe microcephaly v9.44 FTO Ida Ertmanska gene: FTO was added
gene: FTO was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: FTO was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FTO were set to 19559399; 26378117; 26740239; 26697951; 37529081
Phenotypes for gene: FTO were set to Growth retardation, developmental delay, facial dysmorphism, OMIM:612938; lethal polymalformative syndrome, Boissel type, MONDO:0013050
Mode of pathogenicity for gene: FTO was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: FTO was set to AMBER
Added comment: PMID: 37529081 Mayman et al., 2023
Case report: female proband homozygous for FTO c.287G>C, p.Arg96Pro.16 months old at time of report. She had numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function, including severe developmental delay. Fetally detected anomalies included polyhydramnios, IUGR (estimated fetal weight <1%), brain anomalies (poor gyral development, small cerebral hemispheres, and Dandy-Walker spectrum anomaly with incompletely rotated vermis, large foramen of Magendie, large cisterna magna, and hydrocephalus), musculoskeletal anomalies (all long bones <5% mean for gestational age without evidence of fracture, thoracic cage 9% mean for gestational age, and disorganized anterior maxillary tooth buds), and cardiovascular (ventricular septal defect, hypoplastic mitral valve, and aortic arch).

PMID: 26697951 Rohena et al., 2016
Report of a homozygous FTO c.965G>A, p.R322Q variant associated with a lethal malformation syndrome in a consanguineous Yemeni family. The 2 affected sibs (male and female) presented with poor growth, microcephaly (<3rd percentile), and cardiac anomalies. Cranial CT of proband A showed severe ventriculomegaly and cerebral atrophy. He also had profound GDD, craniosynostosis, bilateral cataracts, cryptorchidism, micrognathia, and other annomalies.
Proband B, his younger sister, had dysmorphic facial features, clinodactyly, mild clubfeet, and truncal hypotonia with mild spasticity. Both individuals died due to respiratory failure, at 6 and 2.5 years old.
Exome seq also detected a homozygous VUS TRIM37 variant in proband B (TRIM37 is associated with AR growth disorder with prenatal onset, including occasional progressive cardiomyopathy, characteristic facial features, failure of sexual maturation, insulin resistance with type 2 diabetes, and an increased risk for Wilms tumor - authors note these characteristic features were not present in the siblings).

PMID: 26740239 Çağlayan et al., 2016
Report of a female patient with a homozygous missense mutation in FTO (c.812A>C, p.His271Pro) and a homozygous nonsense mutation p.Arg403X in CETP. No CNVs. Method: WES. CETP is associated with AD Hyperalphalipoproteinemia in OMIM (143470). Parents are second cousins.
Proband presented with microcephaly (head circumference was 41 cm (<2nd percentile) and 9 months old and 47cm (<3rd percentile) at 5 yrs 5 mo), developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia, bilateral hearing loss, and other various phenotypic abnormalities. She had low LDL cholesterol and high HDL cholesterol; diagnosed with CETP-related hyperalphalipoproteinemia.
Western blot analysis demonstrated no changes in patient FTO. Q-PCR analysis revealed slightly decreased levels of FTO expression in patient cells compared to controls.

PMID: 26378117 Daoud et al., 2016
Report of a 21-month-old female with growth retardation and developmental delay, harbouring a homozygous mutation in FTO: p.(Arg316Gln). She presented with distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. Seq method: Targeted NGS panels of 4000+ genes.

PMID: 19559399 Boissel et al. 2009
Report of a consanguineous Palestinian Arab family in which 9 individuals had a severe multiple congenital anomaly syndrome with death by age 3 years. Clinical features dysmorphic facial features, retrognathia, severe failure to thrive in infancy, IUGR (3/9), heart defects (6/9: VSD, AVD, PDA, 4 had hypertrophic cardiomyopathy), severe developmental delay (9/9), microcephaly, lissencephaly, seizures, Dandy-Walker malformation, and other more variable features. Affected individuals were homozygous for FTO:c.947G>A, p.Arg316Gln. Method: autozygosity mapping + targeted analysis of 28 genes on chromosome 16q12.

FTO is associated with AR Growth retardation, developmental delay, facial dysmorphism, OMIM:612938 (OMIM accessed 23rd Oct 2026).
Sources: Literature
Severe microcephaly v9.38 ATRX Eleanor Williams Phenotypes for gene: ATRX were changed from Mental retardation-hypotonic facies syndrome, X-linked, 309580 (Microcephaly); Alpha-thalassemia/mental retardation syndrome, 301040 (Microcephaly) to Intellectual disability-hypotonic facies syndrome, X-linked, OMIM:309580; intellectual disability-hypotonic facies syndrome, X-linked, 1, MONDO:0010663; Alpha-thalassemia/impaired intellectual development syndrome, OMIM:301040; alpha thalassemia-X-linked intellectual disability syndrome, MONDO:0010519
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
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
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
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: 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.; to: 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.
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023
Summary from OMIM 620819: 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.; to: 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.
Severe microcephaly v9.28 DNA2 Ida Ertmanska changed review comment from: PMID: 37055165 Di Lazzaro Filho et al., 2023; to: PMID: 37055165 Di Lazzaro Filho et al., 2023
Summary from OMIM 620819: 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.
Severe microcephaly v9.23 CDK6 Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.

Individuals in PMID:23918663 (see review by Rebecca Foulger) had severe microcephaly of -4 SD and -6SD.
Severe microcephaly v9.23 CDK6 Ida Ertmanska changed review comment from: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.; to: PMID: 41856556 Isik et al., 2026
Report of a female child (Case 3, 7.5 yrs old) homozygous for a CDK6 missense variant NM_001145306: c.461C>T, (p.Thr154Ile) with microcephaly, brain atrophy, neutropenia and ovarian failure. Variant not present in gnomAD v4.1.1. Seq method: WES, parents confirmed carriers by Sanger seq. Parents are consanguineous.
Microcephaly was severe, with head circumference (HC) of 41 cm/−7.3 SD for age. HC at birth was 30 cm/−2.48 SD. In addition, she had moderate intellectual disability, dysmorphic facial features, and cerebral atrophy and hypomyelination on MRI.
Severe microcephaly v9.23 ZNHIT3 Ida Ertmanska Added comment: Comment on list classification: There are now 2 unrelated probands reported with biallelic missense variants in ZNHIT3 and PEHO syndrome, including microcephaly. However, the severity is not stated in PMID: 28335020. A supportive znhit3 knockdown model in zebrafish showed a syndromic presentation with microcephaly. Hence, this gene can only be rated Amber with the current evidence. It was tagged for promotion to Green on Paediatric disorders - additional genes, to ensure inclusion on R27.
Severe microcephaly v9.21 ZNHIT3 Ida Ertmanska changed review comment from: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.; to: PMID: 39252897 Rahman et al., 2024 - PRE-PRINT
Family with 2 fetal cases with isolated hydrops. Both individuals comp het for ZNHIT3 c.40T>C p.Cys14Arg & c.251_254delAAGA variants.
Functional evidence: overexpression of previously reported pathogenic ZNHIT3 variants in HEK293T cells decreases the translational output significantly relative to WT control cells.

PMID: 31048081 Õunap et al., 2019
Report of a female patient (Estonian) with Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy (PEHO) syndrome and comp het ZNHIT3 variants c.92C>T p.(Ser31Leu) & c.41G>T p.(Cys14Phe). Variant p.(Cys14Phe) has 52 alleles reported in gnomAD v4.1.1 (no homozygotes). Unaffected parents het for a variant each.
She had severe muscular hypotonia, profound developmental delay, seizures (onset at 10 months), hypotonia, feeding difficulties, limb edema, and absent visual fixation, diagnosed with blindness at 17 months (pale and small disks, and temporal disk pallor noted). Brain MRI showed cerebral, cerebellar and brainstem atrophy and thin corpus callosum. Progressive microcephaly also noted: OFC -0.5 SD at birth, OFC 46.5 cm (−2.5SD) at 3.5 yrs, and OFC 47 cm (−4 SD) and 8.5 yrs.

PMID: 28335020 Anttonen et al., 2017
Study of 23 Finnish individuals with PEHO syndrome, as well as 40 Finnish and 47 non-Finnish patients with PEHO-like features.
All patients were homozygous for a ZNHIT3:c.92C>T, p.Ser31Leu (NM_004773.4) variant - present in gnomAD 4.1.1 at MAF= 0.004411 in the Finnish population, however no homozygotes reported.
Shared patient phenotype: progressive cerebellar atrophy, microcephaly at birth (severity not stated), optic atrophy, limb oedema, hypotonia, infantile spasms with hypsarrhythmia, profound motor and intellectual disability.

Functional: morpholino knockdown of znhit3 in zebrafish resulted in microcephaly, structural cerebellar anomalies and pericardiac oedema. These phenotypes were rescued by co-injection of human WT ZNHIT3 mRNA. Overexpression of WT or p.Ser31Leu - bearing human ZNHIT3 mRNA did not induce any defects. Hence, authors pose p.Ser31Leu is a LoF variant.

FUNCTIONAL EVIDENCE:
PMID: 40178020 Yang, Xin, and Dean, 2025 - CRISPR/Cas9 used to create a mouse znhit3 -/- knockout model. Absence of ZNHIT3 led to decreased snoRNA and rRNA abundance which causes defects of ribosomes and mRNA splicing. Microinjection of Znhit3 cRNA partially rescues the phenotype and confirms that ZNHIT3 is required for mRNA translation during preimplantation development.
Severe microcephaly v9.20 ZNHIT3 Ida Ertmanska Phenotypes for gene: ZNHIT3 were changed from PEHO syndrome, 260565; microcephaly to Progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; PEHO syndrome, OMIM:260565; PEHO syndrome, MONDO:0009841
Severe microcephaly v9.18 COPB1 Luke Stuart changed review comment from: Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.; to: COPB1 is associated with Baralle-Macken syndrome, OMIM:619255 (accessed 08/2026).

Macken et al., 2021 (PMID 33632302): six affected females from two families are reported, identified via whole exome or genome sequencing; homozygous COPB1 c.957+1G>T in two probands from a Polish kindred (with aberrant splicing and loss of function confirmed via functional assay), and COPB1 c.1651T>G p.(Phe551Val) homozygous in four probands from a Saudi family. Five of six subjects had microcephaly (− 2 SD); 3/6 had severe microcephaly (> 3SD) (two from family 1, one from family 2). In a Xenopus model, CRISPR disruption of copb1 partially recapitulated the human phenotype, causing microcephaly and cataracts. In vitro transfection studies showed abnormal Beta-COP localisation resulting from the p.(Phe551Val) variant with retention within the Golgi and defective Golgi-to-ER recycling, plus mildly reduced protein stability.

Khalid et al., 2025 (PMID 40396222) report an additional two paediatric siblings from a consanguineous Pakistani family with a homozygous missense COPB1 c.2693G>T (p.Arg898Leu) and consistent phenotype, identified via WES. In addition to severe intellectual disability, both patients presented with severe microcephaly and cataracts.

A green rating is recommended based on at least three unrelated affected families with three distinct homozygous pathogenic loss of function variants segregating with disease, with supporting functional evidence and consistent phenotype comprising severe intellectual disability with variable microcephaly and cataracts.
Severe microcephaly v9.12 VPS36 Ida Ertmanska changed review comment from: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature; to: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.

VPS36 is not yet associated with a disease entity in OMIM, ClinGen, or Gene2Phenotype (resources accessed 27th July 2026).
Sources: Literature
Severe microcephaly v9.12 VPS36 Ida Ertmanska gene: VPS36 was added
gene: VPS36 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: VPS36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS36 were set to 28600779; 42362802
Phenotypes for gene: VPS36 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS36 was set to AMBER
Added comment: PMID: 42362802 Chaurasia et al., 2026
Family 21 - VPS36 exon2-3 deletion - 3 affected sibs, one deceased (8yrs)
Family 51 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 15 months and 3 years
Family 52 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 2 affected sibs, died at 4 months and 21 months
Family 53 - consanguineous parents; VPS36 c.1103G>A, p.Arg368His - 3 affected sibs, deceased; 2 unaffected sibs not genotyped
Probands confirmed homozygous, unaffected parents heterozygous. Families 51-53 = 2 Pakistani and 1 Saudi Arabian family. F51 and F53 (Pakistani) were found to have common ancestry, but F52 had a different haplotype.
Phenotypic spectrum of 6 genotyped affected individuals: microcephaly (5/6), motor & speech delay (6/6), ID (5/5 assessed), seizures (5/6), spasticity (5/5), CC agenesis (6/6), cerebellar atrophy (4/6), ventriculomegaly (5/5).

PMID: 28600779 Monies et al., 2017
Individual 16W-0233 - Saudi Arabian patient, homozygous for VPS36:NM_001282169:exon14:c.894-2->T - phenotype: Speech delay, intellectual disability.
Sources: Literature
Severe microcephaly v9.4 MED17 Ida Ertmanska reviewed gene: MED17: Rating: AMBER; Mode of pathogenicity: None; Publications: 20950787, 26004231, 30345598, 36508181; Phenotypes: Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v9.2 VPS51 Ida Ertmanska gene: VPS51 was added
gene: VPS51 was added to Severe microcephaly. Sources: Literature
Q2_26_promote_green tags were added to gene: VPS51.
Mode of inheritance for gene: VPS51 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS51 were set to 30624672; 31207318; 40176246; 40565173
Phenotypes for gene: VPS51 were set to Pontocerebellar hypoplasia, type 13, OMIM:618606; pontocerebellar hypoplasia, type 13, MONDO:0032831; neurodevelopmental disorder, MONDO:0700092
Review for gene: VPS51 was set to GREEN
Added comment: PMID: 40565173 Aygun et al., 2025
2 sibs exhibiting developmental delay, a thin corpus callosum, severe intellectual disability, epilepsy, microcephaly, hearing loss, and dysphagia. Both homozygous for a c.1511C>T; p.Thr504Met VPS51 variant.

PMID: 40176246 Bhanudeep & Koneti, 2025
Proband: 15 month old boy with severe global developmental delay, failure to thrive, microcephaly, generalized hypotonia, nystagmus, Brisk DTRs. Neuroimaging showed diffuse hypomyelinated white matter, severely hypoplastic corpus callosum, and cerebral and cerebellar atrophy. WES revealed a homozygous VPS51 duplication p.Lys126_Met132dup.

PMID: 30624672 (2019) - 6-year-old girl with severe global developmental delay, pontocerebellar abnormalities, microcephaly, hypotonia, epilepsy and several systemic and peripheral dysfunctions. Exome sequencing revealed compound heterozygous variants in VPS51 ([c.2232delC; p.Asp745Thrfs*93];[c.1468C>T; p.Arg490Cys]). Functional studies of both variants indicate impaired function of the mutant protein.

PMID: 31207318 (2019) - two sisters with a homozygous three bp in-frame deletion (c.1419_1421del; p.Phe474del) in VPS51 associated with developmental delay, absent speech, severe ID and microcephaly. Development in both sisters was initially unremarkable; however, following an episode of fever (at 1 and 12 months of age, respectively), pyschomotor development was severely delayed. At 30 months and 9 years of age, respectively, neither sister had any language. No functional studies of the variant or patient cells were undertaken.
Sources: Literature
Severe microcephaly v8.40 NRDC Ida Ertmanska gene: NRDC was added
gene: NRDC was added to Severe microcephaly. Sources: Literature
Q1_26_promote_green tags were added to gene: NRDC.
Mode of inheritance for gene: NRDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRDC were set to 41734767
Phenotypes for gene: NRDC were set to microcephaly, MONDO:0001149; neurodevelopmental disorder, MONDO:0700092; Optic neuropathy, HP:0001138
Review for gene: NRDC was set to GREEN
Added comment: PMID: 41734767 Pehlivan et al., 2026
Report of 14 individuals from nine unrelated families carrying homozygous NRDC pathogenic variants (some reported previously). Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), eye/visual abnormalities (5/7 - 3 with optic atrophy, 1 with nystagmus, and 1 case of visual inattentiveness), and abnormal brain imaging studies ranging from diffuse atrophy to lissencephaly (8/11). The identified variants include two splice, three frameshift, and three missense variants.

NRDC is not yet associated with a phenotype in OMIM (accessed 9th Mar 2026).
Sources: Literature
Severe microcephaly v8.27 EIPR1 Achchuthan Shanmugasundram changed review comment from: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature; to: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 January 2026), Gene2Phenotype or ClinGen.
Sources: Literature
Severe microcephaly v8.26 EIPR1 Achchuthan Shanmugasundram gene: EIPR1 was added
gene: EIPR1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: EIPR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EIPR1 were set to 41058046
Phenotypes for gene: EIPR1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: EIPR1 was set to GREEN
Added comment: PMID:41058046 (2025) reported the identification of five EIPR1 homozygous missense variants (c.835C>G/ p.Arg279Gly, c.813C>G/ p.His271Gln, c.694C>T/ p.Arg232Trp, c.47G>A/ p.Arg16His and c.419T>A/ p.Val140Asp) in eight individuals from six unrelated families with a neurological disorder featuring a spectrum of global neurodevelopmental delay, microcephaly, ataxia, spasticity, delayed myelination, callosal hypoplasia, cerebellar atrophy, walking and speech impairments, dysmorphic facies, and neutropenia. Microcephaly was present in five patients from three unrelated families, of which three patients from two families had Severe microcephaly (OFC beyond -3SD).

There is also functional evidence available from cellular studies using a heterologous transfection system, kin fibroblasts from one of the Arg279Gly affected individuals and zebrafish knockout model. Knockout of the orthologous eipr1 in zebrafish resulted in neurodevelopmental and locomotor defects consistent with the clinical phenotype of the human patients.

This gene has not yet been associated with any phenotypes in OMIM (last accessed 05 December 2025), Gene2Phenotype or ClinGen.
Sources: Literature
Severe microcephaly v8.22 SNAPIN Achchuthan Shanmugasundram gene: SNAPIN was added
gene: SNAPIN was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPIN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPIN were set to 26539891; 40930097
Phenotypes for gene: SNAPIN were set to Neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, OMIM:621393
Review for gene: SNAPIN was set to AMBER
Added comment: PMID:26539891 (2015) reported whole exome sequencing of 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. One of these patients was identified with homozygous variant in SNAPIN gene (c.163C>T/ p.Arg55Trp). The patient displayed intellectual disability, microcephaly, cortical atrophy, bulbar and cerebellar hypoplasia, sensorineural polyneuropathy and hypotonia. The severity of microcephaly is not available in the publication.

PMID:40930097 (2025) reported six patients from five unrelated families presenting with neuroanatomical, craniofacial, and skeletal anomalies and were identified with homozygous variants in SNAPIN gene. This included four foetuses from three unrelated families (had nonsense or splice site variants - c.91G>T/ p.Glu31Ter, c.144−1G>A & c.112C>T/ p.Gln38Ter) and two unrelated patients aged eight years old and one year old (had missense variants - c.147G>C/ p.Glu49Asp & c.163C>T/ p.Arg55Trp). The eight-year-old patient had severe microcephaly (−8 SD), while severity of microcephaly was not recorded for one-year-old patient.

Functional evidence is also available from zebrafish gene ablation models, which recapitulated human-relevant disease phenotypes.

This gene has been associated with relevant phenotype in OMIM (MIM #621393, last accessed on 02 January 2026), but not yet in Gene2Phenotype or ClinGen.
Sources: Literature
Severe microcephaly v8.6 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Severe microcephaly. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Severe microcephaly v7.17 PTPMT1 Arina Puzriakova gene: PTPMT1 was added
gene: PTPMT1 was added to Severe microcephaly. Sources: Literature
watchlist tags were added to gene: PTPMT1.
Mode of inheritance for gene: PTPMT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPMT1 were set to 39279645
Phenotypes for gene: PTPMT1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: PTPMT1 was set to AMBER
Added comment: New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature
Severe microcephaly v7.2 CCDC88A Arina Puzriakova Added comment: Comment on list classification: There are now at least 7 individuals from 4 unrelated families with biallelic variants in the CCDC88A gene (PMID: 26917597; 30392057; 37798908; 39334473), described to a PEHO-like syndrome with universal features including ID, epilepsy, microcephaly and optic nerve/cerebellar atrophy.

Sufficient unrelated cases with the same phenotype to promote this gene to green at the next GMS panel update.
Severe microcephaly v6.7 TTC5 Arina Puzriakova Added comment: Comment on phenotypes: Relevant phenotype has now been added to OMIM - Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, OMIM:619244
Severe microcephaly v6.7 TTC5 Arina Puzriakova Phenotypes for gene: TTC5 were changed from Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system to Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, OMIM:619244
Severe microcephaly v4.77 ATRIP Arina Puzriakova Publications for gene: ATRIP were set to
Severe microcephaly v4.76 ATRIP Arina Puzriakova Mode of inheritance for gene: ATRIP was changed from to BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v4.75 ATRIP Arina Puzriakova Phenotypes for gene: ATRIP were changed from MPD; microcephalic primordial dwarfism; severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism to Microcephalic primordial dwarfism; Severe microcephaly (-10 SD), micrognathia, dental crowding, small earlobes, delayed bone age, and symmetric dwarfism
Severe microcephaly v4.70 ATR Arina Puzriakova Publications for gene: ATR were set to
Severe microcephaly v4.69 ATR Arina Puzriakova Phenotypes for gene: ATR were changed from MPD; microcephalic primordial dwarfism; Seckel syndrome 1, 210600; MICROCEPHALIC PRIMORDIAL DWARFISM I to Seckel syndrome 1, OMIM:210600; Microcephalic primordial dwarfism
Severe microcephaly v4.34 DOHH Arina Puzriakova Phenotypes for gene: DOHH were changed from DOHH associated neurodevelopmental disorder to Neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, OMIM:620066
Severe microcephaly v3.7 ISCA-37408-Loss Arina Puzriakova Phenotypes for Region: ISCA-37408-Loss were changed from PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect to Dysmorphic features, moderate to severe intellectual disability, microcephaly and renal anomalies
Severe microcephaly v2.301 DROSHA Sarah Leigh gene: DROSHA was added
gene: DROSHA was added to Severe microcephaly. Sources: Expert Review Amber,Literature
locus-type-rna-micro, Q2_22_rating tags were added to gene: DROSHA.
Mode of inheritance for gene: DROSHA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DROSHA were set to 35405010
Phenotypes for gene: DROSHA were set to Global developmental delay; Intellectual disability; Seizures; Cerebral white matter atrophy; Abnormality of the corpus callosum; Abnormality of movement; Stereotypic behavior; Abnormality of head or neck; Short foot
Penetrance for gene: DROSHA were set to unknown
Mode of pathogenicity for gene: DROSHA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Severe microcephaly v2.254 ARF3 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

Based on the available evidence, there is currently not enough evidence to support a gene-disease association, therefore this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:34346499, individual 1 also has severe microcephaly (-3.3SD), spasticity, cerebellum atrophy and brainstem atrophy. Individual 2 does not have microcephaly, but has cerebellar hypoplasia.

As only 1 patient has severe microcephaly. This gene has been given a Red rating.
Severe microcephaly v2.238 MED17 Ivone Leong Phenotypes for gene: MED17 were changed from Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668 to Microcephaly, postnatal progressive, with seizures and brain atrophy, OMIM:613668
Severe microcephaly v2.217 NUF2 Zornitza Stark gene: NUF2 was added
gene: NUF2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NUF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUF2 were set to 33721060
Phenotypes for gene: NUF2 were set to microcephaly; short stature; bilateral vocal cord paralysis; micrognathia; atrial septal defect
Review for gene: NUF2 was set to RED
Added comment: PMID: 33721060 - de novo missense variant identified in one male patient with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect.
Sources: Literature
Severe microcephaly v2.152 TRAPPC6B Arina Puzriakova Phenotypes for gene: TRAPPC6B were changed from Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862 to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, OMIM:617862
Severe microcephaly v2.150 PTPN23 Eleanor Williams changed review comment from: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly confirmed in 2 cases, a further 3 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.; to: Associated with Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity #618890 in OMIM,

Severe microcephaly (OFC > 3 SD below mean) confirmed in 1 case, a further 4 cases with microcephaly reported.

PMID:31395947 - Bend et al 2020 - 7 patients with biallelic variants in PTPN23. 2 have microcephaly noted (1 with occipito-frontal head circumference (OFC) −3SD along with severe growth restriction, in the other the degree is not noted). In a 3rd case borderline microcephaly is reported (10th percentile).

PMID:29899372 - Smigiel et al 2018 - 1 patient with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy and compound heterozygous PTPN23 variants (c.1902C>G;p.(Asn634Lys), c.2974delC;p.(Leu992Tyrfs*168) identified by WES. OFC at birth was 30 cm (2 cm below 3 percentile), weight 2320 g (300 g below 3 percentile), length 52 cm (50–90 percentile),

PMID: 29090338 - Sowada et al 2017- 1 patient with developmental and epileptic encephalopathy with compound heterozygous PTPN23 variants (c.3586C>T (p.Arg1196*) and c.1595C>T (p.Pro532Leu)). OFC at birth was 31 cm (− 2.6 SD) but weight was 50th and length 26th percentile.

PMID: 27848944 - Trujillano et al 2017 - 1 patient with homozygous c.904A>G p.(M302V) variant in PTPN23 and microcephaly reported as part of the clinical phenotype. No details as to severity of the microcephaly. They classify the variant as a VUS.

PMID: 25558065 - Alazami et al 2015 - 1 patient with a variant (NM_015466:c.3995G >
T:p.R1332L) in PTPN23 and Global developmental delay, epilepsy and brain atrophy. Microcephaly not mentioned in publication, however in Bend et al 2020 Table 1 says this patient has progressive microcephaly.
Severe microcephaly v2.101 HPDL Arina Puzriakova gene: HPDL was added
gene: HPDL was added to Severe microcephaly. Sources: Literature
Q2_21_rating tags were added to gene: HPDL.
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086; 33188300
Phenotypes for gene: HPDL were set to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613
Review for gene: HPDL was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'probable' disease confidence for 'HPDL Neurodegenerative Disease' in Gene2Phenotype.

At least 34 cases from 21 unrelated families with a paediatric-onset spastic movement disorder and biallelic variants in this gene (PMIDs: 32707086 and 33188300). There is broad clinical variability ranging from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated HSP. Microcephaly of relevant severity (HC ≤ 3 SD) was observed in 13/30 cases.

Supportive functional studies were reported, including localization of HPDL protein to the mitochondria and muscle fibre abnormalities and a KO mouse model displaying features of seizures, early lethality, smaller brain sizes, and cellular apoptosis.
Sources: Literature
Severe microcephaly v2.74 TRAPPC12 Arina Puzriakova Phenotypes for gene: TRAPPC12 were changed from Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669 to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669; Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696
Severe microcephaly v2.72 TRAPPC12 Arina Puzriakova reviewed gene: TRAPPC12: Rating: GREEN; Mode of pathogenicity: None; Publications: 28777934, 32369837; Phenotypes: Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, OMIM:617669, Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, MONDO:0044696; Mode of inheritance: None
Severe microcephaly v2.20 EXOC7 Zornitza Stark gene: EXOC7 was added
gene: EXOC7 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: EXOC7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOC7 were set to 32103185
Phenotypes for gene: EXOC7 were set to brain atrophy; seizures; developmental delay; microcephaly
Review for gene: EXOC7 was set to GREEN
gene: EXOC7 was marked as current diagnostic
Added comment: 4 families with 8 affected individuals with brain atrophy, seizures, and developmental delay, and in more severe cases microcephaly and infantile death. Four novel homozygous or comp.heterozygous variants found in EXOC7, which segregated with disease in the families. They showed that EXOC7, a member of the mammalian exocyst complex, is highly expressed in developing human cortex. In addition, a zebrafish model of Exoc7 deficiency recapitulates the human disorder with increased apoptosis and decreased progenitor cells during telencephalon development, suggesting that the brain atrophy in human cases reflects neuronal degeneration.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC6B Zornitza Stark gene: TRAPPC6B was added
gene: TRAPPC6B was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC6B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC6B were set to 28626029; 28397838; 31687267
Phenotypes for gene: TRAPPC6B were set to Neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, MIM# 617862
Review for gene: TRAPPC6B was set to GREEN
gene: TRAPPC6B was marked as current diagnostic
Added comment: Five unrelated families reported with autosomal recessive neurodegenerative disorder characterised by global developmental delay, severe intellectual disability with poor or absent speech and autistic stereotypic behaviors, microcephaly, early-onset generalized seizures, and hypotonia.
Sources: Expert list
Severe microcephaly v2.20 TRAPPC12 Zornitza Stark gene: TRAPPC12 was added
gene: TRAPPC12 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: TRAPPC12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAPPC12 were set to 32369837; 28777934
Phenotypes for gene: TRAPPC12 were set to Encephalopathy, progressive, early-onset, with brain atrophy and spasticity, MIM# 617669
Review for gene: TRAPPC12 was set to GREEN
gene: TRAPPC12 was marked as current diagnostic
Added comment: Four families reported with a severe progressive encephalopathy characterized by microcephaly, global developmental delay, and hearing loss.
Sources: Expert list
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
Severe microcephaly v2.20 PTPN23 Zornitza Stark gene: PTPN23 was added
gene: PTPN23 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: PTPN23 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTPN23 were set to 31395947; 29899372; 29090338; 27848944; 25558065
Phenotypes for gene: PTPN23 were set to Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, MIM# 618890
Review for gene: PTPN23 was set to GREEN
Added comment: Over 10 families reported with an autosomal recessive neurologic disorder characterised by global developmental delay apparent from early infancy, poor overall growth often with microcephaly (6/10), impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum.
Sources: Expert list
Severe microcephaly v2.19 MED17 Zornitza Stark gene: MED17 was added
gene: MED17 was added to Severe microcephaly. Sources: Expert list
Mode of inheritance for gene: MED17 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MED17 were set to 20950787; 30345598; 26004231
Phenotypes for gene: MED17 were set to Microcephaly, postnatal progressive, with seizures and brain atrophy, MIM# 613668
Review for gene: MED17 was set to GREEN
gene: MED17 was marked as current diagnostic
Added comment: Five individuals from four families reported initially, founder effect for p.Leu371Pro. Two additional families reported since with different variants, one family with milder phenotype.
Sources: Expert list
Severe microcephaly v1.62 ATRIP Louise Daugherty reviewed gene: ATRIP: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ATRX Louise Daugherty reviewed gene: ATRX: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.62 ATR Louise Daugherty reviewed gene: ATR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.61 ATRIP Louise Daugherty Source NHS GMS was added to ATRIP.
Severe microcephaly v1.61 ATRX Louise Daugherty Source NHS GMS was added to ATRX.
Severe microcephaly v1.61 ATR Louise Daugherty Source NHS GMS was added to ATR.
Severe microcephaly v1.37 ISCA-37408-Loss Louise Daugherty Region: ISCA-37408-Loss was added
Region: ISCA-37408-Loss was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37408-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37408-Loss were set to 16963482; 22579565; 18245392
Phenotypes for Region: ISCA-37408-Loss were set to PMID: 16963482 idiopathic intellectual disability including moderate to severe intellectual disability, autism/autistic features, microcephaly, structural brain anomalies including cortical dysplasia/pachygyria, renal anomalies (multicystic kidney, hydronephrosis), digital camptodactyly, visual impairment, strabismus, neuromotor deficits, communication and attention impairments, and a distinctive pattern of craniofacial features. Dysmorphic craniofacial features include progressive microcephaly, flat occiput, widened inner canthal distance, small palpebral fissures, ptosis, long and straight eyelashes, broad and high nasal root extending to a widened, prominent nasal tip with elongated, smooth philtrum, rounding of the upper vermillion border and everted lower lips. PMID: 18245392 A 32-year-old, mentally retarded male was referred to our centre for further clinical genetic analysis. He was born to non-consanguineous parents after 42 weeks gestation with a birth weight of 3500 g. He had a healthy older brother. In the neonatal period he was hypotonic and at 8 weeks of age he underwent surgery because of an inguinal hernia with removal of an atrophic right testis. His motor development was severely delayed with sitting at 3.5 years and walking at 5 years of age. Speech was poorly developed, characterised by the usage of only a few words. During infancy an optic nerve hypoplasia was diagnosed, and during childhood he frequently suffered from luxations of the patellae, which required surgery. At the age of 32 years his height is 163 cm (_3 SDS) and head circumference 52.5 cm (_2.5 SDS). He has a narrow receding forehead, widened inner canthal distance of 3.5 cm (90th centile), normal outer canthal distance of 8.5 cm (25th centile), telecanthus, short and down slanting palpebral fissures, epicanthal folds, ptosis, long, straight eyelashes, high nasal bridge, low set large ears, flat philtrum, small mouth with high, narrow palate and retrognathia. The thorax is broad with increased internipple distance and slight gynaecomastia. A recent renal ultrasound revealed multiple cysts in the left, dystrophic kidney and two uncomplicated cysts in the enlarged, right kidney. The patient has a normally sized phallus with absent right testis and small left testis. His hands show a simian crease right and tapering fingers with broad proximal interphalangeal joints. He shows sandal gaps on both flat feet with clinodactyly of the fourth and fifth toes (and more); 612513; PMID: 22579565 severe developmental delay, congenital microcephaly, intractable epilepsy, and renal anomalies, as well as a congenital choledochal cyst which has not been previously reported in other patients with this cytogenetic defect
Severe microcephaly ATRX Rebecca Foulger edited their review of ATRX
Severe microcephaly ATRX Rebecca Foulger classified ATRX as green
Severe microcephaly ATRX Rebecca Foulger commented on ATRX
Severe microcephaly ATRX emma baple reviewed ATRX
Severe microcephaly ATRIP Alice Gardham marked ATRIP as ready
Severe microcephaly ATR Alice Gardham marked ATR as ready
Severe microcephaly ATR Alice Gardham classified ATR as green
Severe microcephaly ATR Alice Gardham reviewed ATR
Severe microcephaly ATRIP Rebecca Foulger commented on ATRIP