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Fetal anomalies v8.20 NUSAP1 Luke Stuart gene: NUSAP1 was added
gene: NUSAP1 was added to Fetal anomalies. 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
Fetal anomalies v1.836 CRIPT Arina Puzriakova Tag for-review was removed from gene: CRIPT.
Fetal anomalies v1.836 CRIPT Arina Puzriakova commented on gene: CRIPT: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Fetal anomalies v1.835 CRIPT Arina Puzriakova Source Expert Review Green was added to CRIPT.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Fetal anomalies v1.727 SCUBE3 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 5 variants reported in 5 unrelated cases, together with supportive functional and mouse model studies (PMID 33308444).; to: Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. PMID 33308444 reports eight SCUBE variants in nine unrelated families, including eighteen affected members. In vtro studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, resulting in dysregulation on bone morphogenetic protein (BMP) signaling and a Scube3−/− mouse showed shared phenotypic features with OMIM:619184. Prenatal growth retardation was evident in 8/11 relevant cases.
Fetal anomalies v1.357 CRIPT Arina Puzriakova Classified gene: CRIPT as Amber List (moderate evidence)
Fetal anomalies v1.357 CRIPT Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Following curation and clinical review it has been agreed that the associated phenotype is fetally-relevant and therefore this gene should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Fetal anomalies v1.357 CRIPT Arina Puzriakova Gene: cript has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.356 CRIPT Arina Puzriakova Tag for-review tag was added to gene: CRIPT.
Fetal anomalies v1.228 CRIPT Rhiannon Mellis gene: CRIPT was added
gene: CRIPT was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies, 615789
Review for gene: CRIPT was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): IUGR and IGF abnormalities
Sources: Expert list
Fetal anomalies v1.195 SCLT1 Rhiannon Mellis gene: SCLT1 was added
gene: SCLT1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SCLT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SCLT1 were set to No OMIM phenotype; Oro-facio-digital syndrome type IX; Senior-Løken Syndrome
Review for gene: SCLT1 was set to GREEN
Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in October 2020. This gene has a Green evidence rating on at least one other related PanelApp panel. Clinical review and curation was performed by Lyn Chitty, Rhiannon Mellis, and Richard Scott. Outcome of review: Confirmed that phenotype is fetally-relevant: add to the Fetal anomalies panel as a Green gene.

Green on related panel(s): Rare multisystem ciliopathy Super panel


Copied from rare multisystem ciliopathies panel:
PMID: 24285566 - Adly et al 2014 - 1 case with index patient with consanguineous Saudi parents and a severe ciliopathy phenotype. He had severe midline cleft lip and palate, microcephaly and choanal atresia. He also had significant eye involvement in the form of severe coloboma, and congenital heart disease (ASD and VSD). He had micropenis. Brain imaging revealed pachygyria and absent corpus callosum. He had abnormal inner ear structures. A splicing mutation was identified in SCLT1 (, NM_144643.2:exon5:c.290+2T>C). This mutation completely abolishes the consensus donor site of exon 5 as confirmed by RTPCR, which showed complete skipping of exon 5 resulting in a frameshift and introduction of a premature stop codon (p.Lys79Valfs*4),

PMID: 28005958 - de Castro-Miró et al 2016 - A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. 1 case with compound heterozygosity (one missense and one splicing altering mutations) in SCLT1 that segregates with the condition in the family (2 affected siblings). Proposed to be causative of early-onset Retinitis Pigmentosa. SCLT1 is a member of the centrosomal/ciliary protein family.

PMID: 28486600 - Li et al 2017 - report a mouse model with mutated Sclt1 gene. The Sclt1-/- mice exhibit typical ciliopathy phenotypes, including cystic kidney, cleft palate and polydactyly.

PMID: 30425282 - Katagiri et al 2018 - a patient with Senior Løken syndrome and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts. Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein.

= 3 cases plus a mouse model and functional evidence that the protein is a ciliary protein.
Sources: Literature
Fetal anomalies v1.155 MN1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Rhiannon Mellis (GOSH). Multiple unrelated individuals (>20) described with a complex developmental disorder and de novo truncating MN1 variants. This gene will be flagged for review to determine whether the phenotype is fetally-relevant and there is enough evidence to include as Green.

Plausible that some features of the disorder, such as craniofacial abnormalities and structural brain anomalies may be detected prenatally. However based on published clinical descriptions, antenatal history was uneventful in most cases - but reports did include fetal brain anomalies (1), NICU admission (1) and IUGR (2). Similarly, neonatal problems were only reported in a few patients but included respiratory issues (3), abnormal ABR (1), congenital diaphragmatic hernia (1), perinatal hypoxia (1), congenital hypothyroidism (1), hearing impairment (1) and SCBU admission (1) (see Supplementary material in PMID: 31834374)
Fetal anomalies v0.197 SPTBN2 Rebecca Foulger Added comment: Comment on phenotypes: Added more informative phenotype description from OMIM (Spinocerebellar ataxia, autosomal recessive 14, 615386) as Gene2Phenotype names the disorder as SCA14.