Ataxia and cerebellar anomalies - childhood onset

Gene: SMG9

Green List (high evidence)

Biallelic SMG9 variants cause a phenotypic spectrum comprising a severe heart and brain malformation syndrome with multisystem congenital malformations and a syndromic neurodevelopmental disorder dominated by intellectual disability, movement abnormalities and ocular signs. Sufficient evidence (described herein) supports structural brain anomalies, including cerebellar anomalies, and childhood-onset ataxia as components of the SMG9 phenotypic spectrum.

Shaheen et al. 2016, PMID 27018474: family 1 IV, c.520_521delCC, p.(Pro174Argfs*12) homozygous. Patient presented with Dandy-Walker malformation with cerebellar vermis hypoplasia and hypoplastic corpus callosum. Family 2, V:1: c.701+4A>G homozygous. Patient presented with Dandy-Walker malformation, brain atrophy and decreased myelination.
The authors generated a severe hypomorphic/null Smg9 allele by CRISPR/Cas9 targeting exon 2. Homozygous embryos showed markedly reduced viability, developmental delay and structural central nervous system abnormalities, supporting a developmental role for SMG9: E15.5: reduced midbrain and hindbrain size on micro-CT; some embryos also had exencephaly. Abnormal brain development was highly penetrant among evaluable homozygotes: 2/2 at E14.5, 7/7 at E15.5 and 2/2 at E18.5.

Altuwaijri et al. 2021, PMID 33609422 patient 1: c.701+4A>G, p.(Tyr197Aspfs*10) homozygous. Cerebellar and pontine atrophy with flattening of the ventral pons, plus generalized brain atrophy was noted.

Lecoquierre et al. 2019, PMID 31390136: c.1177C>T, p.(Gln393*) homozygous. Patient presented with enlarged/dysmorphic fourth ventricle and Blake pouch cyst, consistent with a posterior-fossa developmental anomaly was noted.

Rahikkala et al. 2022, PMID 35087184 reported 5 males, ranging in age from 24 to 56 years, from 3 unrelated Finnish families with variable intellectual disability, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. All were homozygous for SMG9 c.551T>C, p.(Val184Ala). Four patients were described as ataxic in childhood.

SMG9 is associated with the relevant phenotypes in OMIM (# 616920 and # 619995), accessed 11/2026.

Sources: Literature

Created: 6 Nov 2026, 12:35 p.m. | Last Modified: 6 Nov 2026, 6:23 p.m.

Panel Version: 9.52

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Heart and brain malformation syndrome, MONDO:0014833; Heart and brain malformation syndrome, OMIM:616920; Neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, OMIM:619995; Complex neurodevelopmental disorder, MONDO:0100038

Publications

• 27018474
• 33609422
• 31390136
• 35087184