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Severe microcephaly v9.62 WDR44 Achchuthan Shanmugasundram Added comment: Comment on list classification: Of nine unrelated families, two of them had severe microcephaly as part of the phenotype. Hence, this gene is rated amber with the current evidence.
Severe microcephaly v9.61 WDR44 Achchuthan Shanmugasundram gene: WDR44 was added
gene: WDR44 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: WDR44 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: WDR44 were set to 38191484
Phenotypes for gene: WDR44 were set to Ciliopathy, MONDO:0005308
Review for gene: WDR44 was set to GREEN
Added comment: WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking.

PMID:38191484 (2024) reported the identification of seven different missense and one nonsense variants in WDR44 gene in 11 male patients from nine families that displayed ciliopathy-related developmental disorder. The patient phenotypic spectrum included developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities.

ID was moderate in three unrelated patients, while mild in five unrelated patients. Learning disability was reported in three patients from two families. Abnormalities in brain MRI findings including CC hypoplasia, enlarged CSF spaces and/ or ventriculomegaly were reported in nine patients from seven families. Severe microcephaly (OFC <-3 SD below mean) were only reported in two unrelated patients.

Upper limb abnormalities including Brachydactyly were reported in six patients from four families, spine abnormalities such as scoliosis were reported in three patients from two families, and lower limb abnormalities such as congenital hip dislocation and/ or toes syndactyly were reported eight patients from six families.

There is also supporting functional evidence available from patient fibroblasts and zebrafish models.

This gene has been associated with relevant phenotype in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (records last accessed on 06 November 2026).
Sources: Literature
Severe microcephaly v9.60 TMEM161B Ida Ertmanska changed review comment from: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported; it is not known if probands with the same variants are related, so best to score as 2 independent families. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature; to: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported; it is not known if probands with the same variants are related, so best to score as 2 independent families. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria. Head circumference unknown.
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs. HC measurements unknown.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature
Severe microcephaly v9.59 TMEM161B Ida Ertmanska changed review comment from: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 38593811 Li et al. 2024
Generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt). No clinical details.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature; to: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported; it is not known if probands with the same variants are related, so best to score as 2 independent families. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature
Severe microcephaly v9.59 TMEM161B Ida Ertmanska changed review comment from: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound.

PMID: 38593811 Li et al. 2024
Generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt). No clinical details.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature; to: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound. All individuals had seizures, with onset in the first few months of life. No cardiovascular abnormalities, no ophthalmic features apart from megalocornea in 1 family.

PMID: 38593811 Li et al. 2024
Generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt). No clinical details.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature
Severe microcephaly v9.59 TMEM161B Ida Ertmanska changed review comment from: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound.

PMID: 38593811 Li et al. 2024
Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt)

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature; to: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound.

PMID: 38593811 Li et al. 2024
Generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt). No clinical details.

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature
Severe microcephaly v9.59 TMEM161B Ida Ertmanska gene: TMEM161B was added
gene: TMEM161B was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: TMEM161B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM161B were set to 36669109; 36669111; 38593811; 37486637
Phenotypes for gene: TMEM161B were set to polymicrogyria, MONDO:0000087; microcephaly, MONDO:0001149
Added comment: PMID: 36669109 Wang et al., 2023
Study of a polymicrogyria (PMG) cohort identified four families with affected children showing nearly identical neocortical PMG. Brain imaging in each showed dramatic symmetrical PMG, without a clear lobar or regional predominance. WES revealed homozygous variants in TMEM161B: c.949C>T; p.W317R in Families I & II, and c.254T>G; p.L85R in Families III and IV. All 4 families were from Egypt and had consanguinity reported. Parents unaffected. Mild microcephaly reported at birth (HC -0.5 to -1.5 SD), progressing to severe at last examination in all 4 probands (head circumference -3 to -4.5 SD). Intellectual disability was moderate to profound.

PMID: 38593811 Li et al. 2024
Individual 10 - 2yo male - het for TMEM161B: c.800+5G>A - shown to cause skipping of exon 8 (141 nt)

PMID: 36669111 Akula et al., 2023
Study describes 3 families with probands either homozygous or compound heterozygous for variants in TMEM161B. Variants described in the article are missense or splice site (splice site was shown in PMID 38593811 to result in skipping of exon 8).
Individual 09DG00538, Family A - presented at birth after normal delivery with intractable seizures, severe microcephaly, and hypotonia/spastic paresis; an MRI revealed diffuse PMG.
Individual UDN172478, Family B- diffuse PMG, pachygyria
4 sibs in Family C - presented with spastic hemiparesis, dysarthria, intellectual disability, and seizures. Diffuse PMG was discovered in the eldest sibling on autopsy; brain imaging unavailable for other sibs.

Article also generated and described TMEM161B null mice which broadly phenocopy the clinical indications described in the 3 families (null mice show holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes).
Sources: Literature
Severe microcephaly v9.58 DRG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with microcephaly, of which it was severe in two families (<-3 SD). There is also functional evidence available for the variants from cell lines suggesting loss-of-function mechanism, and mouse model showing pre-weaning lethality. Hence, this gene can be promoted to green rating in the next GMS update.
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 v9.10 SNW1 Achchuthan Shanmugasundram changed review comment from: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature; to: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes in OMIM (last accessed 24 July 2026), Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
Sources: Literature
Severe microcephaly v9.10 SNW1 Achchuthan Shanmugasundram gene: SNW1 was added
gene: SNW1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: SNW1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SNW1 were set to 40608414
Phenotypes for gene: SNW1 were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: SNW1 was set to GREEN
Added comment: PMID:40608414 (2025) reported the identification of nine different heterozygous variants in nine unrelated patients presenting with a neurodevelopmental disorder with features of moderate to severe intellectual disability (moderate in three, profound in one and severe in four), severe microcephaly (8 of 9), seizures (7 of 9), brain malformations (corpus callosum hypoplasia in 4 individuals and Dandy-Walker malformation in another 2), and facial dysmorphisms (7 of 9). Pregnancy was medically terminated in one case (individual 7) and hence brain malformation and facial dysmorphism were the only reported features among the ones listed above.

Variants were confirmed as de novo in eight individuals, whereas inheritance could not be tested in one due to adoption. The variants included missense (2), splice site (3), in-frame deletions (3), frameshift (1) and start loss (1).

There is also functional evidence available from in vitro studies, and Drosophila and human embryonic stem cell-derived cerebral organoids models. Knockdown of the SNW1 ortholog Bx42 in Drosophila impaired CNS development, marked by reduced brain lobe size and loss of NSC proliferation, and these phenotypes were rescued by reintroduction of human SNW1, indicating conserved function. In cerebral organoids, SNW1 haploinsufficiency recapitulated the microcephaly phenotype, characterised by impaired neural progenitor proliferation and increased apoptosis.

This gene has not yet been associated with relevant phenotypes either in OMIM, Gene2Phenotype or ClinGen, but rated green on appropriate panels in PanelApp Australia.
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 v8.18 ISCA-46300-Loss Arina Puzriakova changed review comment from: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen; to: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review (Last Evaluated:10/24/2025): Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Severe microcephaly v8.18 ISCA-46300-Loss Arina Puzriakova Region: ISCA-46300-Loss was added
Region: ISCA-46300-Loss was added to Severe microcephaly. Sources: ClinGen
Q3_25_promote_green tags were added to Region: ISCA-46300-Loss.
Mode of inheritance for Region: ISCA-46300-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-46300-Loss were set to 27399968; 22180641
Phenotypes for Region: ISCA-46300-Loss were set to Developmental delays/intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features
Review for Region: ISCA-46300-Loss was set to GREEN
Added comment: https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-46300

ClinGen review: Deletion of the 15q24 recurrent region (C-D) has been reported in at least 4 patients with a syndromic clinical phenotype characterized by developmental delays (speech and motor), intellectual disability, brain anomalies, craniofacial abnormalities, hypermobile joints, digital findings, and other variable clinical features. Two additional patients have also been reported with atypical deletions encompassed by the 15q24 LCR C-D region, but with breakpoints proximal to LCR D. Both of these patients had a similar clinical presentation to patients with the typical 15q24 LCR C-D deletion. Parental studies have demonstrated that each of the deletions in this region (6 total) represent de novo events. Case-control data are currently uninformative due to the rarity of this deletion. The known haploinsufficient gene SIN3A is thought to represent the critical gene within this region, as SIN3A sequence level have a similar clinical presentation to recurrent deletion.
Sources: ClinGen
Severe microcephaly v8.13 UGGT1 Achchuthan Shanmugasundram gene: UGGT1 was added
gene: UGGT1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: UGGT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UGGT1 were set to 40267907
Phenotypes for gene: UGGT1 were set to congenital disorder of glycosylation, MONDO:0015286
Review for gene: UGGT1 was set to AMBER
Added comment: PMID:40267907 (2025) reported biallelic UGGT1 variants (either homozygous or compound heterozygous) in fifteen individuals from ten unrelated families of various descents as a cause of congenital disorder of glycosylation. There are a total of nine different UGGT1 variants identified from these patients including one nonsense variant, four insertion or deletion (indel) variants and four missense variants. All variants are ultra-rare or absent from gnomAD v.4.1.0.

The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability (severe ID reported in all tested individuals - ten from six unrelated families), seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). However, severe secondary microcephaly (postnatal OFC beyond a Z-score < -3) was only reported in five patients from four families.

Molecular studies showed that pathogenic UGGT1 variants impair UGGT1 glucosylation and catalytic activity, disrupt mRNA splicing, or inhibit endoplasmic reticulum (ER) retention.

This gene has been associated with UGGT1-related congenital disorder of glycosylation with neurodevelopmental impairment phenotype on the DD panel of Gene2Phenotype with 'moderate' rating, but not yet with any phenotypes in OMIM.
Sources: Literature
Severe microcephaly v8.11 INPP4A Achchuthan Shanmugasundram changed review comment from: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature; to: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Severe microcephaly v8.10 INPP4A Achchuthan Shanmugasundram gene: INPP4A was added
gene: INPP4A was added to Severe microcephaly. Sources: Literature
Q3_25_promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 39315527; 40748307; 40772914
Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092; microcephaly, MONDO:0001149
Review for gene: INPP4A was set to GREEN
Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. 15 patients from 10 families presented with microcephaly, of which 11 patients from eight families had severe microcephaly (OFC < -3 SD below mean). Three of these 15 patients had nonsense variants in exon 4, nine patients had LoF variants downstream of exon 4, while the remaining three had missense variants.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. The severity of microcephaly was not provided in the report.

PMID:40748307 (2025) reported two brothers with homozygous splice variant in INPP4A gene (c.106+1G>A/ p.Gly36Aspfs*22). They presented with global developmental delay, short stature, microcephaly (severity not reported), limb ataxia, generalised hypotonia, and mild limb weakness. They both had cerebellar anomalies.
Sources: Literature
Severe microcephaly v8.3 CRNKL1 Achchuthan Shanmugasundram gene: CRNKL1 was added
gene: CRNKL1 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRNKL1 were set to https://doi.org/10.1016/j.ajhg.2025.05.013
Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder, MONDO:0100038
Review for gene: CRNKL1 was set to GREEN
Added comment: There are 10 unrelated patents identified with de novo missense variants in the spliceosomal component CRNKL1, where nine of them harboured one of the two missense variants affecting the same amino acid residue, Arg 267 (p.Arg267Cys & p.Arg267His), while the tenth patient harboured a different variant (p.Arg301Gly). All affected individuals share a common and specific phenotype: profound pre- and post-natal microcephaly (8 of 10 patients), with pontocerebellar hypoplasia (9 patients), seizures (8 patients), and severe intellectual disability (8 patients).

Microinjection of mRNA encoding Crnkl1 variant into a zebrafish model caused a severe lack of brain development accompanied by a significant reduction in proliferating cells and widespread cellular stress, as indicated by p53 staining. RNA sequencing analysis of injected zebrafish embryos showed broad transcriptomic changes, with altered expression of neuronal and cell cycle genes.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Sources: Literature
Severe microcephaly v7.21 LRRC8C Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39623139 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
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 v7.15 PNPLA8 Sarah Leigh Added comment: Comment on publications: PMID: 39082157 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Severe microcephaly v7.10 WDR47 Achchuthan Shanmugasundram Added comment: Comment on publications: PMID:39609633 paper was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Severe microcephaly v6.4 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will remain amber.; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will made red.
Severe microcephaly v6.3 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
The ClinGen Gene-Disease Validity score for this gene is "Disputed" (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3d41cebe-5490-419d-882d-4f3c6856be07-2021-05-05T160000.000Z), therefore, this gene will remain amber.
Severe microcephaly v6.1 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
Severe microcephaly v6.1 DPP6 Sarah Leigh changed review comment from: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviors characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).; to: DPP6 variants have been associated with Intellectual developmental disorder, autosomal dominant 33 in OMIM (#: 616311), but not with a phenotype in Gen2Phen. To date two monoallelic variants have been associated with OMIM: 616311 in two unrelated families, where the affected individuals all had microcephaly and intellectual disability (PMID:23832105). Various Dpp6 knock-down mouse models, showed that these mice had significantly lower body and brain weights in comparison to wildtype and displayed behaviours characteristic of reduced learning abilities and impaired memory (PMID: 21943606; 23832105; 29651237).
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram changed review comment from: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature; to: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. Head circumference measurements at time of last visit were available in eight individuals (from six families) and were consistent with microcephaly (−3.8 to −2.7 SD from mean for age). Of these four individuals from three families had severe microcephaly (head circumference beyond 3 SD from mean for age).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.23 GRM7 Achchuthan Shanmugasundram gene: GRM7 was added
gene: GRM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: GRM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GRM7 were set to 2248644; 32286009
Phenotypes for gene: GRM7 were set to Neurodevelopmental disorder with seizures, hypotonia, and brain abnormalities, OMIM:618922
Review for gene: GRM7 was set to GREEN
Added comment: PMID:32286009 reported eleven individuals from six unrelated families identified with three different biallelic variants and presenting with a neurodevelopmental disorder comprising severe to profound global developmental delays, intellectual disability, seizures, hypotonia, microcephaly and brain abnormalities. This is also supported by functional evidence from knockout mouse models, where absence of metabotropic glutamate receptor 7 alters the phenotypes within the domains of social behavior, associative learning, motor function, epilepsy and sleep (PMID:32248644).

This gene has also been associated with relevant phenotypes in both OMIM (MIM #618922) and in Gene2Phenotype (with 'strong' rating in the DD panel).
Sources: Literature
Severe microcephaly v4.18 TRA2B Achchuthan Shanmugasundram changed review comment from: This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature; to: PMID:36549593 reported 12 individuals from 11 unrelated families identified with 11 different heterozygous variants in TRA2B gene. The variants arose de novo in 10 families, while the variant was inherited from father to son in one family. 6 variants were expected to disrupt the translation start site in exon 1 (start-loss variants), 3 were expected to disrupt the splicing process at the exon 2/3 boundary (splice-affecting variants), and the remaining 2 were expected to produce a premature stop codon (truncating variants).

These patients presented with a neurodevelopmental disorder comprising developmental delay/ intellectual disability (in all patients), axial or global hypotonia (10 patients), delayed motor milestones (all patients), behavioural issues (8 patients), speech impairment (9 patients), epilepsy (7 patients, initial presentation as infantile spasms in 6 and unclassified epileptic encephalopathy in 1), brain abnormalities (10 patients) and microcephaly (5 patients). Of 5 unrelated cases with microcephaly, only two cases had severe microcephaly (head circumference beyond 3 standard deviations below the mean for the age).

In addition, functional studies in mice showed that heterozygous knockout mice developed normal, while complete knockout mice cannot develop embryonically.

This gene has already been associated with phenotypes in Gene2Phenotype (with 'moderate' rating in the DD panel), but not in OMIM.
Sources: Literature
Severe microcephaly v2.247 ARCN1 Ivone Leong changed review comment from: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040; to: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040 describes another case. "3.5-yr-old Caucasian/Peruvian/Native American boy with microcephaly, severe global developmental delay, and multiple congenital abnormalities. At birth he was documented to have a small ventricular septal defect (which was closed by 3 wk), a patent foramen ovale, rhizomelic shortening of extremities on clinical examination, pectus carinatum, and underdeveloped genitalia including severe penoscrotal hypospadias and cryptorchidism." OFC at birth was just above 10th centile, at 3.5 yr OFC is below 3rd centile but no actual measurements were given. Microarrays identified a 95-kb loss at 12q23.2 including exons 1–4 of the NUP37 gene and exons 1–9 of the PARPBP gene, which were deemed nondiagnostic (neither parents had this deletion). A heterozygous variant was also found in HSPG2 (c.9893 C > T, p. Pro3298Leu). Biallelic variants in this gene is associated with skeletal disorders that did not fit the patient's phenotype and as the patient is heterozygous for a variant in HSPG2 it was deemed that this variant was not causative. WGS identified a de novo splice variant in ARCN1. mRNA studies showed that the variant caused retention of part of an intron in the transcript. The authors deemed the ARCN1 variant as the causative variant in this patient.
Severe microcephaly v2.247 ARCN1 Ivone Leong Added comment: Comment on publications: PMID:27476655. OMIM description of the patients, "exhibited rhizomelic short stature (4/4) as well as microcephaly (3/4), micrognathia (4/4), laxity of the small joints (3/4), and developmental delay (4/4). Other variable features included posterior cataract (1/4), cleft palate (1/4), ventricular septal defect (1/4), cryptorchidism (1/2), seizures (1/4), and autism (1/4)."

Additional publications. PMID: 31075182 describes a 5th case with de novo loss-of-function variant in ARCN1. Head circumference at birth (prematurely after 33 + 3 weeks of pregnancy) was 27.3 cm (<3rd percentile). The publication says the patient presented with microcephaly; however, I cannot find any recent head circumference measurements (child is 23 months old). From the paper "we report a de novo loss-of-function mutation in the delta-COP subunit of COPI, associated with microcephaly, retrognathia, muscular hypotonia, short stature, rhizomelic shortening, and transiently hypoglycosylation during febrile infections."

PMID: 33154040
Severe microcephaly v2.103 PPP1R35 Arina Puzriakova gene: PPP1R35 was added
gene: PPP1R35 was added to Severe microcephaly. Sources: Other
watchlist tags were added to gene: PPP1R35.
Mode of inheritance for gene: PPP1R35 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PPP1R35 were set to Primary microcephaly
Added comment: Conference poster (Genomics of Rare Disease 2021) - 'Biallelic frameshift indel in PPP1R35 as a cause of primary microcephaly' by Dawood et al, Baylor College of Medicine -

Proband from a Turkish consanguineous family with primary microcephaly (-4.3 SD at birth, -6.1 SD by 42 months) and GDD. Brain imaging showed thinning of corpus collosum, mild cerebellar volume loss, increased extra-axial CSF spaces, pachygyria, dysmorphic ventricular system and delayed myelination of the internal capsule. Exome sequencing revealed a biallelic frameshifting indel in the PPP1R35 gene (c.753_*3delGGAAGCGTAGACCinsCG; p.Trp251Cysfs*22), resulting in deletion of the canonical stop codon in the last exon. Sequencing of unaffected parents and 2 unaffected sibs confirmed segregation with the phenotype. Droplet digital PCR demonstrated expression of mutant mRNA, with comparable gene expression levels observed for mutant and wild-type alleles in fibroblasts.

Authors note a second Iranian consanguineous family in literature with two sibs with microcephaly and the same, p.Trp251Cysfs*22 variant - however, this paper could not be found in PubMed.
Sources: Other
Severe microcephaly v2.87 AP4E1 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. Rating Amber but there is sufficient evidence to rate Green at the next GMS panel update (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but details regarding head circumference were mostly unavailable. At least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).; to: Comment on list classification: New gene added by Zornitza Stark. Rating Amber with recommendation of review by the GMS team to assess whether there is sufficient evidence to support a Green rating (added 'for-review' tag)

At least 21 individuals from 11 unrelated families reported in literature with variants in this gene (PMID: 32979048). Microcephaly was observed in 14/16 cases but precise details regarding head circumference were mostly omitted (no relevant info was provided for the remaining 5 patients). However, at least 5 individuals (2 families) had microcephaly of relevant severity to this panel (OFC ≤ -3 SD) (see PMIDs: 21620353 and 20972249).
Severe microcephaly v2.44 LMNB2 Sarah Leigh edited their review of gene: LMNB2: Added comment: Not associated with a relevant phenotype in OMIM or in Gen2Phen. PMID 33033404 reports five individuals with heterozygous variants in LMNB2. One of these cases was de novo for c.160A>C p.N54H (NM_032737.4) and the remaining cases had c.1192G>A, p.Glu398Lys (NM_032737.4), which was shown to be de novo in two cases, inherited from the unaffected mother (who was mosaic for the variant) and the inheritance in the remaining case was not established. All of these cases had moderate to severe developmental delay and microcephaly.; Changed rating: GREEN
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 v2.12 NCAPD2 Arina Puzriakova gene: NCAPD2 was added
gene: NCAPD2 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: NCAPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NCAPD2 were set to 27737959; 28097321; 31056748
Phenotypes for gene: NCAPD2 were set to Microcephaly 21, primary, autosomal recessive, 617983
Review for gene: NCAPD2 was set to GREEN
Added comment: Associated with phenotype in OMIM and a possible gene for Microcephaly with short stature in G2P.

PMID: 27737959 (2016) - A homozygous splice site variant (c.4120+2T>C, p.Asp1374Glyfs*29) in NCAPD2 was detected in a 3-year-old male with severe microcephaly (OFC -11.9 SD), severe ID, autistic-like behaviours, and no speech. The variant was found in a heterozygous state in both unaffected parents and was not present in the ExAC database. Functional studies indicated that the variant disrupted condensin-dependent mitotic chromosome integrity, providing supporting evidence for pathogenicity.

PMID: 28097321 (2017) - In two affected cousins from a consanguineous family with mild ID, intrauterine growth retardation, short stature, and microcephaly. Homozygous missense variants were found in NCAPD2 (c.23T>C, p.Phe8Ser), but also in ENO2 (c.710C>T, p.Thr237Met). Variants segregated with disease in the family, but no further functional studies were undertaken of the variants or patient cells.

PMID: 31056748 (2019) - In a 13-year-old female with severe microcephaly (OFC < -3), mild ID (IQ 59), poor learning performance, sloping forehead and reduced cerebral cortex size, exome sequencing revealed a homozygous variant in NCAPD2 (c.3477+2T>C, p.Gly1160Valfs*16). Progressive microcephaly was also apparent in a sibling of the proband, a male fetus which was terminated at 34 weeks of pregnancy. The same homozygous variant was identified in the fetus, while parents were heterozygotes and an unaffected brother was homozygous for the other allele. No further functional studies of the variant or patient cells were performed.
Sources: Literature
Severe microcephaly v1.62 NIN Louise Daugherty reviewed gene: NIN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.61 NIN Louise Daugherty Source NHS GMS was added to NIN.
Severe microcephaly v1.37 ISCA-37425-Gain Louise Daugherty Region: ISCA-37425-Gain was added
Region: ISCA-37425-Gain was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37425-Gain was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37425-Gain were set to 23913520; 23599694
Phenotypes for Region: ISCA-37425-Gain were set to Microcephaly, short stature and developmental delay; short stature, microcephaly, learning disability or mild to moderate ID, and distinctive facial features comprising periorbital fullness, short palpebral fissures, a long nose with broad or long nasal tip, a smooth philtrum and a thin upper lip vermilion. Behavioral problems, ocular and minor hand anomalies may be associated.
Severe microcephaly v1.37 ISCA-37406-Loss Louise Daugherty Region: ISCA-37406-Loss was added
Region: ISCA-37406-Loss was added to Primary Microcephaly - Microcephalic Dwarfism Spectrum. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37406-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37406-Loss were set to 10573006; 16783566
Phenotypes for Region: ISCA-37406-Loss were set to PMID: 10573006 death in infancy, accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, renal agenesis (patient 1), severe neonatal seizures (patient 2). PMID 16783566: failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectivelyFrom Genetics Home Reference: short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes; 610543
Severe microcephaly NIN Rebecca Foulger marked NIN as ready
Severe microcephaly NIN Rebecca Foulger commented on NIN