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Intellectual disability

Gene: SCYL2

Amber List (moderate evidence)
SCYL2 (SCY1 like pseudokinase 2)
EnsemblGeneIds (GRCh38): ENSG00000136021
EnsemblGeneIds (GRCh37): ENSG00000136021
OMIM: 616365, Gene2Phenotype
SCYL2 is in 3 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are now 3 unrelated individuals reported in literature with biallelic SCYL2 nonsense variants and syndromic Arthrogryposis multiplex congenita, including severe global developmental delay. There are also 2 probands with biallelic missense variants in SCYL2, presenting with language delay and ASD. Hence, this gene can be promoted to Green on the Intellectual disability panel.
Created: 4 Nov 2026, 5:10 p.m. | Last Modified: 4 Nov 2026, 5:17 p.m.
Panel Version: 11.86
PMID: 40243816 Zamel et al., 2025
Report of a male proband from Egypt. Parents are consanguineous. He presented at birth with dysmorphic facial features, microcephaly, bilateral talipes equinovarus deformities, multiple mild contractures and poor sucking. At 18 months, his microcephaly was severe (43.3 cm, <2%, z-score −3.15). Bilateral optic atrophy and autonomic dysfunction were noted. Brain MRI at 13 months showed agenesis of the corpus callosum, ponto-cerebellar volume reduction, and non-specific white matter abnormalities. Patient had recurrent infections and died of respiratory distress at 22 months. He was found to be homozygous for 2 SCYL2 variants: c.1721T>C, (p.L574P) and c.1726C>G, (p.P576A). He was also homozygous for 3 rare variants in other genes (none associated with arthrogryposis). Not sure about the contribution of SCYL2 to the phenotype; biallelic missense variants are at odds with previously reported AMC cases.

PMID: 39169672 Malbos et al., 2024
Reported 2 individuals with biallelic LoF variants in SCYL2 with syndromic Arthrogryposis multiplex congenita, and 2 other individuals with biallelic missense variants in SCYL2, presenting with isolated developmental delay:
Case 1 - prenatal findings included bilateral clubfoot, CC agenesis, retrognathia, and reduced fetal movement. Pregnancy was terminated at 27 weeks. Autopsy revealed absence of testes and features of arthrogryposis: irreducible flexed arms, clenched hands, and flexion contractures of fingers.
Case 2 - 2 month old boy born to consanguineous parents; he presented with arthrogryposis, CC agenesis, cerebral and cerebellar atrophy, cryptorchidism, global dev delay, hip dysplasia, and inguinal hernia.
Case 3 - 7yo boy born to a consanguineous couple; he had language delay and normal motor development, diagnosed with ASD; he also had left cryptorchidism, mild dysmorphic features, and inguinal hernia. Brain MRI was normal.
Case 4 - 8yo boy born to a non-consanguineous couple. He had severe language delay, microcephaly, clinodactyly and syndactyly. Diagnosed with ASD. Brain MRI not performed.

PMID: 39138116 Thauvin-Robinet et al., 2024
Prenatal exome sequencing study. Patient I.15 had a variant in SCYL2 and presented with foot malposition, corpus callosum agenesis, and microretrognathia. Did not find details of the variant.

PMID: 31960134 Seidahmed et al., 2020
2 unrelated consanguineous families reported with different SCYL2 nonsense variants and a syndromic form of severe AMC comprising microcephaly, absent corpus callosum, optic atrophy, limb fractures, profound GDD, and early lethality.

SCYL2 is associated with AR Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766 (OMIM accessed 4th Nov 2026).
Sources: Literature
Created: 4 Nov 2026, 5:06 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766

Publications

Created: 4 Nov 2026, 5:06 p.m.
Last Modified: 4 Nov 2026, 5:17 p.m.
Panel version: 11.83

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766
  • Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, MONDO:0032903
Tags
Q4_26_promote_green
OMIM
616365
Clinvar variants
Variants in SCYL2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

4 Nov 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: SCYL2 were changed from Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766 to Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766; Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, MONDO:0032903

4 Nov 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: scyl2 has been classified as Amber List (Moderate Evidence).

4 Nov 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: scyl2 has been classified as Amber List (Moderate Evidence).

4 Nov 2026, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ida Ertmanska (Genomics England Curator)

gene: SCYL2 was added gene: SCYL2 was added to Intellectual disability. Sources: Literature Q4_26_promote_green tags were added to gene: SCYL2. Mode of inheritance for gene: SCYL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCYL2 were set to 31960134; 39138116; 39169672; 40243816 Phenotypes for gene: SCYL2 were set to Arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, OMIM:618766 Review for gene: SCYL2 was set to GREEN