Ataxia and cerebellar anomalies - childhood onset

Gene: PAX6

Comment on list classification: As reviewed by Luke Stuart, there are two unrelated patients with heterozygous PAX6 variants and with evidence ataxia and/or a cerebellar syndrome phenotype. Although PAX6 knockout mice showed a primary role for PAX6 in cerebellar development, but did not recapitulate ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency.

There is sufficient evidence available for the association of PAX6 biallelic loss-of-function variants with a severe, prenatal/neonatal-onset neurodevelopmental disorder. However, reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities. Hence, this phenotype is not relevant for this panel.

Hence, the gene should be demoted to amber and the MOI should be updated to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.

Created: 7 Oct 2026, 1:21 p.m. | Last Modified: 7 Oct 2026, 1:21 p.m.

Panel Version: 9.38

I don't know

Early literature suspected PAX6 as the causative gene for Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation), but direct sequencing repeatedly found no PAX6 mutations in classic Gillespie cases. Linkage analysis in affected families showed the disease trait segregates independently from chromosome 11p markers flanking PAX6 (Glaser et al., 1994; PMID 8188215). The causative gene was identified as ITPR1.

PAX6 biallelic loss-of-function causes a severe, prenatal/neonatal-onset neurodevelopmental disorder characterised by anophthalmia/microphthalmia and major CNS malformations, including agenesis of the corpus callosum, olfactory bulb aplasia/hypoplasia, brainstem hypoplasia, cortical malformations, and cerebellar dysplasia/hypoplasia; reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities (Glaser et al., 1994, PMID: 7951315; Schmidt-Sidor et al., 2009, PMID: 20054790; Solomon et al., 2010, PMID: 19876904). A rare paediatric report described a 4-year-old proband with compound heterozygous PAX6 variants (1x missense affecting the paired domain and 1x nonsense); they presented with structural brain anomalies including agenesis of the corpus callosum, hypoplastic pons and vermis (absent inferiorly), possible Dandy-Walker malformation, pituitary and hypothalamic hypoplasia; attribution of these phenotypic features to PAX6 is confounded by the proband's dual diagnosis including trisomy 21 (Solomon et al., 2009 (PMID 19876904).

Isolated reports describe heterozygous PAX6 variants associated with neurological manifestations, including ataxia or cerebellar dysfunction:

Ticho et al., 2006 (PMID: 17148041): A patient described as having "atypical Gillespie syndrome" presented with mild hand tremor and learning disability but no reported ataxia or structural cerebellar abnormalities on neuroimaging. Sequencing identified a heterozygous PAX6 splice-site variant, IVS2+2T>A.
Graziano et al., 2007 (PMID 17595013): described a 9.5-year-old girl with bilateral aniridia, ataxia, and intellectual disability; she carried a de novo heterozygous nonsense variant, PAX6 p.(Trp257Ter).
Dansault et al., 2007 (PMID 17417613): In a large family carrying the c.655A>G p.S74G variant, all affected individuals exhibited a mild but consistent cerebellar syndrome. The most severely affected individual had a clear static cerebellar syndrome. MRI findings included hypoplasia of the anterior commissure and absence of the pineal gland in one individual. Despite the consistent neurological phenotype, no specific structural cerebellar abnormalities were identified.

Conclusion: Two unrelated PAX6 families with heterozygous variants showed evidence ataxia and/or a cerebellar syndrome phenotype, the latter without any recognisable cerebellar malformation. PAX6 knockout mice delineate a primary role of PAX6 in cerebellar development, though are not known to recapitulate an ataxia phenotype, nor cerebellar phenotype in the context of haploinsufficiency (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)). An amber rating with monoallelic inheritance is proposed.

Created: 11 Sep 2026, 4:51 p.m. | Last Modified: 7 Oct 2026, 9:50 a.m.

Panel Version: 9.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Aniridia (OMIM:106210); cerebellar ataxia (MONDO:0000437)

Publications

• 17148041
• 8188215
• 7951315
• 20054790
• 19876904
• 17417613
• 8213068
• 16979618
• 19876904