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Severe microcephaly v9.56 NUSAP1 Luke Stuart changed review comment from: Nonsense-mediated decay (NMD)-escaping truncating variants in NUSAP1 are associated with a syndromic neurodevelopmental phenotype characterised by congenital microcephaly, profound developmental impairment, neonatal-onset refractory epilepsy, and structural brain malformations.

Mo et al., 2023 (PMID 37005340). A de novo NUSAP1 variant, c.1209C>A, p.(Tyr403Ter), was identified by trio exome sequencing in two unrelated probands. Both had severe congenital microcephaly (<1st centile and <5th centile), severe/profound developmental delay, neonatal-onset refractory epilepsy, complex structural brain malformations, and hypotonia. Transcript studies suggested NMD-escape. Both cases were characterised by fetal anomalies on prenatal USS (microcephaly, agenesis of the CC, small hindbrain in individual II‐2 and microcephaly, inter‐hemispheric cyst in individual II‐1).

Jacob et al., 2026 (PMID 42706591): Trio exome and genome sequencing in two probands, ID#1 and ID#2, identified de novo heterozygous truncating variants in NUSAP1: c.1264C>T, p.(Arg422Ter), and c.1213C>T p.(Gln405Ter), respectively. Seizures began on the first day of life in ID#1 and on day 8 of life in ID#2; congenital microcephaly was also noted (<1st percentile in ID#1). Additional shared features included developmental delay, profound intellectual disability, and variable structural abnormalities on brain MRI. Both cases where characterised by abnormal fetal USS (intrauterine growth restriction and oligohydramnios in ID#1, and microcephaly and ventriculomegaly in ID#2).
The authors also reported unchanged NUSAP1 expression by RNA sequencing in one affected individual. They delineated a critical region at the 3′ end of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls (gnomAD), whereas frameshift variants producing C-terminal elongations appear tolerated, consistent with gene-level nonsense constraint (https://www.deciphergenomics.org/gene/NUSAP1/overview/protein-genomic-info)

Four unrelated affected individuals are reported (with three distinct de novo NMD-escaping truncating variants) and a consistent phenotype including severe-profound developmental impairment and intellectual disability, epilepsy, severe microcephaly, and structural brain anomalies. A green rating is recommended for intellectual disability, early onset or syndromic epilepsy, severe microcephaly, and fetal anomalies panels at the next GMS panel update.

NUSAP1 is not currently associated with any disease/ phenotype in OMIM, Gene2Phenotype, ClinGen (10/2026).
Sources: Literature; to: Nonsense-mediated decay (NMD)-escaping truncating variants in NUSAP1 are associated with a syndromic neurodevelopmental phenotype characterised by congenital microcephaly, profound developmental impairment, neonatal-onset refractory epilepsy, and structural brain malformations.

Mo et al., 2023 (PMID 37005340). A de novo NUSAP1 variant, c.1209C>A, p.(Tyr403Ter), was identified by trio exome sequencing in two unrelated probands. Both had severe congenital microcephaly (OFC <-3 S.D. in both), severe/profound developmental delay, neonatal-onset refractory epilepsy, complex structural brain malformations, and hypotonia. Transcript studies suggested NMD-escape. Both cases were characterised by fetal anomalies on prenatal USS (microcephaly, agenesis of the CC, small hindbrain in individual II‐2 and microcephaly, inter‐hemispheric cyst in individual II‐1).

Jacob et al., 2026 (PMID 42706591): Trio exome and genome sequencing in two probands, ID#1 and ID#2, identified de novo heterozygous truncating variants in NUSAP1: c.1264C>T, p.(Arg422Ter), and c.1213C>T p.(Gln405Ter), respectively. Seizures began on the first day of life in ID#1 and on day 8 of life in ID#2; congenital microcephaly was also noted (<1st percentile, <-3 S.D. in ID#1). Additional shared features included developmental delay, profound intellectual disability, and variable structural abnormalities on brain MRI. Both cases where characterised by abnormal fetal USS (intrauterine growth restriction and oligohydramnios in ID#1, and microcephaly and ventriculomegaly in ID#2).
The authors also reported unchanged NUSAP1 expression by RNA sequencing in one affected individual. They delineated a critical region at the 3′ end of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls (gnomAD), whereas frameshift variants producing C-terminal elongations appear tolerated, consistent with gene-level nonsense constraint (https://www.deciphergenomics.org/gene/NUSAP1/overview/protein-genomic-info)

Four unrelated affected individuals are reported (with three distinct de novo NMD-escaping truncating variants) and a consistent phenotype including severe-profound developmental impairment and intellectual disability, epilepsy, severe microcephaly, and structural brain anomalies. A green rating is recommended for intellectual disability, early onset or syndromic epilepsy, severe microcephaly, and fetal anomalies panels at the next GMS panel update.

NUSAP1 is not currently associated with any disease/ phenotype in OMIM, Gene2Phenotype, ClinGen (10/2026).
Sources: Literature
Severe microcephaly v9.54 NUSAP1 Luke Stuart gene: NUSAP1 was added
gene: NUSAP1 was added to Severe microcephaly. Sources: Literature
Q4_26_promote_green tags were added to gene: NUSAP1.
Mode of inheritance for gene: NUSAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NUSAP1 were set to 37005340; 42706591
Phenotypes for gene: NUSAP1 were set to microcephaly(MONDO:0001149); neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities(MONDO:0030063)
Mode of pathogenicity for gene: NUSAP1 was set to Other
Review for gene: NUSAP1 was set to AMBER
Added comment: Nonsense-mediated decay (NMD)-escaping truncating variants in NUSAP1 are associated with a syndromic neurodevelopmental phenotype characterised by congenital microcephaly, profound developmental impairment, neonatal-onset refractory epilepsy, and structural brain malformations.

Mo et al., 2023 (PMID 37005340). A de novo NUSAP1 variant, c.1209C>A, p.(Tyr403Ter), was identified by trio exome sequencing in two unrelated probands. Both had severe congenital microcephaly (<1st centile and <5th centile), severe/profound developmental delay, neonatal-onset refractory epilepsy, complex structural brain malformations, and hypotonia. Transcript studies suggested NMD-escape. Both cases were characterised by fetal anomalies on prenatal USS (microcephaly, agenesis of the CC, small hindbrain in individual II‐2 and microcephaly, inter‐hemispheric cyst in individual II‐1).

Jacob et al., 2026 (PMID 42706591): Trio exome and genome sequencing in two probands, ID#1 and ID#2, identified de novo heterozygous truncating variants in NUSAP1: c.1264C>T, p.(Arg422Ter), and c.1213C>T p.(Gln405Ter), respectively. Seizures began on the first day of life in ID#1 and on day 8 of life in ID#2; congenital microcephaly was also noted (<1st percentile in ID#1). Additional shared features included developmental delay, profound intellectual disability, and variable structural abnormalities on brain MRI. Both cases where characterised by abnormal fetal USS (intrauterine growth restriction and oligohydramnios in ID#1, and microcephaly and ventriculomegaly in ID#2).
The authors also reported unchanged NUSAP1 expression by RNA sequencing in one affected individual. They delineated a critical region at the 3′ end of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls (gnomAD), whereas frameshift variants producing C-terminal elongations appear tolerated, consistent with gene-level nonsense constraint (https://www.deciphergenomics.org/gene/NUSAP1/overview/protein-genomic-info)

Four unrelated affected individuals are reported (with three distinct de novo NMD-escaping truncating variants) and a consistent phenotype including severe-profound developmental impairment and intellectual disability, epilepsy, severe microcephaly, and structural brain anomalies. A green rating is recommended for intellectual disability, early onset or syndromic epilepsy, severe microcephaly, and fetal anomalies panels at the next GMS panel update.

NUSAP1 is not currently associated with any disease/ phenotype in OMIM, Gene2Phenotype, ClinGen (10/2026).
Sources: Literature
Severe microcephaly v9.34 CRIPT Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CRIPT.
Severe microcephaly v9.34 CRIPT Ida Ertmanska changed review comment from: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. Hence, this gene can be promoted to Green at the next update.; to: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. 5/6 probands had microcephaly reported, though the severity only reached -2.5 to -2.7 SD in 3 of these cases. Hence, this gene can be promoted to Green at the next update, with an expert_review tag added to ensure that consistent near-severe microcephaly is in scope of this panel.
Severe microcephaly v9.31 CRIPT Ida Ertmanska Tag Q3_26_promote_green tag was added to gene: CRIPT.
Severe microcephaly v9.31 CRIPT Ida Ertmanska commented on gene: CRIPT: Comment on list classification: There are now 6 unrelated individuals reported in literature with biallelic CRIPT variants and Rothmund-Thomson syndrome, with microcephalic dwarfism being a consistent feature. Hence, this gene can be promoted to Green at the next update.
Severe microcephaly v9.31 CRIPT Ida Ertmanska Phenotypes for gene: CRIPT were changed from Ida Ertmanska (Genomics England Curator) Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347 to Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347
Severe microcephaly v9.30 CRIPT Ida Ertmanska Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies, 615789 to Ida Ertmanska (Genomics England Curator) Rothmund-Thomson syndrome, type 3, OMIM:615789; Rothmund-Thomson syndrome type 3, MONDO:0014347
Severe microcephaly v9.29 CRIPT Ida Ertmanska Publications for gene: CRIPT were set to 27250922 Leduc et al., 2016 describe a female with biallelic mutations in CRIPT, presenting with short stature, dysmorphic features, microcephaly and hypopigmented macules. They detect a c.8G>A (p.C3Y) missense variant inherited from the mother in exon 1, and a 1,331?bp deletion encompassing exon 1, inherited from the father; 24389050 Shaheen et al., 2014 report 2 cases: they examined cases with Short stature with microcephaly and distinctive facies (OMIM:615789). In a 3 year old boy they identified homozygosity for a 2bp insertion (c.133_134insGG) predicted to cause premature termination (Ala45GlyfsTer87). They also analyzed DNA from the first-cousin parents of a deceased affected male Saudi Arabian infant. The patient was presumed homozygous for a loss of function variant based on the heterozygous status of the parents.
Severe microcephaly v9.28 CRIPT Ida Ertmanska reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: 24389050, 27250922, 36630262, 37013901; Phenotypes: Rothmund-Thomson syndrome, type 3, OMIM:615789, Rothmund-Thomson syndrome type 3, MONDO:0014347; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v8.21 KBTBD2 Arina Puzriakova Added comment: Comment on list classification: Adding to this panel as Amber as despite there being 3 unrelated cases, a specific description of the phenotype is not provided in one case (GDX6) making it challenging to make genotype-phenotype correlations. Microcephaly is reported in the other two individuals, however the severity is not specified. Based on the current evidence additional support is needed before this gene can be added to a diagnostic panel.
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 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 v2.194 MCM7 Arina Puzriakova gene: MCM7 was added
gene: MCM7 was added to Severe microcephaly. Sources: Literature
Mode of inheritance for gene: MCM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MCM7 were set to 33654309; 34059554
Phenotypes for gene: MCM7 were set to Meier-Gorlin syndrome; Microcephaly; Intellectual disability
Review for gene: MCM7 was set to AMBER
Added comment: MCM7 is a component of the MCM complex, a DNA helicase which is essential for DNA replication. Other components have been linked to disease with phenotypes including microcephaly and ID. Currently, MCM7 is not associated with any phenotype in OMIM or G2P.

- PMID: 33654309 (2021) - Two unrelated individuals with different compound het variants in MCM7 but disparate clinical features. One patient had typical Meier-Gorlin syndrome (including growth retardation, microcephaly, congenital lung emphysema, absent breast development, microtia, facial dysmorphism) whereas the second case had a multi-system disorder with neonatal progeroid appearance, lipodystrophy and adrenal insufficiency. While small at birth, the second patient did not demonstrate reduced stature or microcephaly at age 14.5 years. Both individuals had normal neurodevelopment.
Functional studies using patient-derived fibroblasts demonstrate that the identified MCM7 variants were deleterious at either transcript or protein levels and through interfering with MCM complex formation, impact efficiency of S phase progression.

- PMID: 34059554 (2021) - Homozygous missense variant identified in three affected individuals from a consanguineous family with severe primary microcephaly, severe ID and behavioural abnormalities. Knockdown of Mcm7 in mouse neuroblastoma cells lead to reduced cell viability and proliferation with increased apoptosis, which were rescued by overexpression of wild-type but not mutant MCM7.
Sources: Literature
Severe microcephaly v2.18 TUBGCP2 Arina Puzriakova gene: TUBGCP2 was added
gene: TUBGCP2 was added to Severe microcephaly. Sources: Literature
for-review tags were added to gene: TUBGCP2.
Mode of inheritance for gene: TUBGCP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TUBGCP2 were set to 31630790
Phenotypes for gene: TUBGCP2 were set to Pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, 618737
Review for gene: TUBGCP2 was set to GREEN
Added comment: Associated with phenotype in OMIM, and a probable gene for Microcephaly and Lissencephaly Spectrum Disorders in G2P.

PMID: 31630790 (2019) - Five patients from four families with biallelic variants in the TUBGCP2 gene. Affected individuals shared phenotypic features that included progressive severe microcephaly (4/4, Z score: -4.0 to -9.0), developmental delay (5/5, mild-severe), seizures (4/5). All patients exhibited lissencephaly-spectrum phenotypes with varying degrees of cortical malformations on brain imaging including pachygyria and subcortical band heterotopia.

All variants segregated with disease in each family. Analysis of fibroblasts derived from one patient with a splice site variant revealed several abnormal transcripts, predicted to result in LoF. No further functional studies of other variants or patient cells were performed.
Sources: Literature
Severe microcephaly v1.62 CRIPT Louise Daugherty reviewed gene: CRIPT: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Severe microcephaly v1.61 CRIPT Louise Daugherty Source NHS GMS was added to CRIPT.
Severe microcephaly CRIPT Rebecca Foulger classified CRIPT as amber
Severe microcephaly CRIPT Rebecca Foulger commented on CRIPT
Severe microcephaly CRIPT Rebecca Foulger classified CRIPT as amber
Severe microcephaly CRIPT Rebecca Foulger added CRIPT to panel
Severe microcephaly CRIPT Rebecca Foulger reviewed CRIPT