Malformations of cortical development

Gene: SCYL2

Green List (high evidence)

Comment on list classification: There are at least 3 unrelated individuals reported in literature with biallelic SCYL2 variants and agenesis of corpus callosum. Hence, this gene can be promoted to Green at the next update.

Created: 5 Nov 2026, 10:48 a.m. | Last Modified: 5 Nov 2026, 10:48 a.m.

Panel Version: 8.18

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: 5 Nov 2026, 10:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

• 31960134
• 39138116
• 39169672
• 40243816