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Fetal anomalies v8.17 PAX6 Achchuthan Shanmugasundram Publications for gene: PAX6 were set to
Fetal anomalies v8.16 PAX6 Luke Stuart edited their review of gene: PAX6: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v8.16 PAX6 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As reviewed by Luke Stuart, there is sufficient evidence available for the association of PAX6 biallelic loss-of-function variants with a severe, prenatal/neonatal-onset neurodevelopmental disorder. Reported cases were stillborn or died in the neonatal period, with only rare survival despite profound developmental abnormalities.

Monoallelic PAX6 variants are associated with developmental eye disorders, including aniridia, microphthalmia, coloboma and foveal hypoplasia. It is unclear whether monoallelic variants are relevant for the fetal anomalies panel. Hence, expert opinion is sought on whether the MOI should be updated to BOTH or Biallelic ONLY.
Fetal anomalies v8.16 PAX6 Achchuthan Shanmugasundram Mode of inheritance for gene: PAX6 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v8.15 PAX6 Achchuthan Shanmugasundram Tag Q3_26_expert_review tag was added to gene: PAX6.
Tag Q3_26_MOI tag was added to gene: PAX6.
Fetal anomalies v8.15 PAX6 Luke Stuart changed review comment from: Biallelic PAX6 variants are associated with severe congenital malformation including structural brain anomalies and aniridia. The paucity of patients reports reflects embryonic/ perinatal lethality associated with biallelic PAX6 loss of function.

Glaser et al. 1994; PMID 7951315: A proband with compound heterozygous nonsense variants, c.607C>T (p.Arg203Ter) and c.1058C>G (p.Ser353Ter), presented with anophthalmia, microcephaly, complete agenesis of the corpus callosum and olfactory bulbs, hypoplasia of the cerebellum and pons, and died in the neonatal period.

Solomon et al., 2010 (PMID 19876904): A surviving patient with compound heterozygous mutations in PAX6 presented with microphthalmia, neonatal diabetes mellitus, hypopituitarism, and microcephaly, as well as trisomy 21. The patient inherited a missense mutation affecting the paired domain from the father (c.112C>T, p.Arg38Trp), who had microcornea and severe cataracts, and a nonsense mutation in HD from the mother (c.718C>T, p.Arg240Ter), who presented with classical familial aniridia. Complex brain anomalies including absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria were noted.

Schmidt-Sidor et al., 2009 (PMID 20054790) described a stillborn fetus; PAX6 c.117_128del12 (affecting the paired domain) and a frameshift variant, c.112delC, were identified in compound heterozygosity; autopsy revealed major CNS abnormalities including complete agenesis of the corpus callosum, cortical malformations and various cerebellar anomalies including cerebellar dysplasia; a similar phenotype was observed in a subsequent pregnancy.

This severe CNS malformation phenotype is recapitulated in the Sey (Small eye) mouse, which carries a PAX6 LoF point mutation c.622G>T (p.Gly208Ter) (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)); Pax6 is produced in cerebellar granule cells and that PAX6 influences the morphogenesis of the whole cerebellum; homozygous Pax6Sey/Sey mice exhibit severe brain malformations, including cerebellar abnormalities, and die perinatally, whereas heterozygous Pax6Sey/+ mice survive and show developmental defects consistent with PAX6 haploinsufficiency.

3 unrelated patients are reported and the biallelic Sey mouse model recapitulates the human phenotype. Thus MOI comprising BOTH monoallelic and biallelic is proposed for the fetal anomalies panel.; to: Biallelic PAX6 variants are associated with severe congenital malformation including structural brain anomalies and aniridia. The paucity of patients reports reflects embryonic/ perinatal lethality associated with biallelic PAX6 loss of function. Monoallelic PAX6 pathogenic variants are associated with developmental eye disorders, including aniridia, microphthalmia, coloboma and foveal hypoplasia. Additional findings associated with PAX6-aniridia are variably reported, including Polymicrogyria (in 2/ 24 individuals reproted in PMID 12731001), structural brain MRI abnormalities affecting the commissures, corpus callosum, pineal gland; cataracts; glaucoma (Williamson et al., 2019 (PMID 31700164); Abouzeid et al. 2009 (PMID 19862335).

Glaser et al. 1994; PMID 7951315: A proband with compound heterozygous nonsense variants, c.607C>T (p.Arg203Ter) and c.1058C>G (p.Ser353Ter), presented with anophthalmia, microcephaly, complete agenesis of the corpus callosum and olfactory bulbs, hypoplasia of the cerebellum and pons, and died in the neonatal period.

Solomon et al., 2010 (PMID 19876904): A surviving patient with compound heterozygous mutations in PAX6 presented with microphthalmia, neonatal diabetes mellitus, hypopituitarism, and microcephaly, as well as trisomy 21. The patient inherited a missense mutation affecting the paired domain from the father (c.112C>T, p.Arg38Trp), who had microcornea and severe cataracts, and a nonsense mutation in HD from the mother (c.718C>T, p.Arg240Ter), who presented with classical familial aniridia. Complex brain anomalies including absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria were noted.

Schmidt-Sidor et al., 2009 (PMID 20054790) described a stillborn fetus; PAX6 c.117_128del12 (affecting the paired domain) and a frameshift variant, c.112delC, were identified in compound heterozygosity; autopsy revealed major CNS abnormalities including complete agenesis of the corpus callosum, cortical malformations and various cerebellar anomalies including cerebellar dysplasia; a similar phenotype was observed in a subsequent pregnancy.

This severe CNS malformation phenotype is recapitulated in the Sey (Small eye) mouse, which carries a PAX6 LoF point mutation c.622G>T (p.Gly208Ter) (Schmahl et al., 1993; PMID 8213068; Quinn et al., 2007; PMID 16979618)); Pax6 is produced in cerebellar granule cells and that PAX6 influences the morphogenesis of the whole cerebellum; homozygous Pax6Sey/Sey mice exhibit severe brain malformations, including cerebellar abnormalities, and die perinatally, whereas heterozygous Pax6Sey/+ mice survive and show developmental defects consistent with PAX6 haploinsufficiency.

3 unrelated patients are reported and the biallelic Sey mouse model recapitulates the human phenotype, thus a green rating for biallelic inheritance is recommended. It is unclear whether monoallelic PAX6-related disease lies within the intended scope of the fetal anomalies panel, thus expert review is requested for monoallelic PAX6-related disease.
Fetal anomalies v8.7 PAX6 Luke Stuart reviewed gene: PAX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 7951315, 19876904, 20054790, 8213068, 16979618; Phenotypes: Corpus callosum, agenesis of (MONDO:0009022); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.311 CYP1B1 Rebecca Foulger edited their review of gene: CYP1B1: Added comment: This gene was re-reviewed in a consistency check by Anna de Burca (Genomics England Clinical Team), and at a Fetal Working Group call on July 19th 2019 by Lyn Chitty, Anna de Burca, Richard Scott, Rhiannon Mellis, Rebecca Foulger and Ellen McDonagh. Outcome of review: Although we wouldn't include Peters anomaly alone on the panel, you can get cataracts with Peters anomaly and therefore include PAX6 and CYP1B1 on this basis.; Changed rating: GREEN
Fetal anomalies v0.311 PAX6 Rebecca Foulger edited their review of gene: PAX6: Added comment: This gene was re-reviewed in a consistency check by Anna de Burca (Genomics England Clinical Team), and at a Fetal Working Group call on July 19th 2019 by Lyn Chitty, Anna de Burca, Richard Scott, Rhiannon Mellis, Rebecca Foulger and Ellen McDonagh. Outcome of review: Although we wouldn't include Peters anomaly alone on the panel, you can get cataracts with Peters anomaly and therefore include PAX6 and CYP1B1 on this basis.; Changed rating: GREEN
Fetal anomalies v0.310 PAX6 Rebecca Foulger Source Expert Review Green was added to PAX6.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Fetal anomalies v0.229 PAX6 Rebecca Foulger Source Expert Review Red was added to PAX6.
Rating Changed from Green List (high evidence) to Red List (low evidence)
Fetal anomalies v0.228 PAX6 Rebecca Foulger edited their review of gene: PAX6: Added comment: This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March and April 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Phenotype is not fetally-relevant. Action taken: Demoted PAX6 gene rating from Green to Red.; Changed rating: RED
Fetal anomalies v0.9 PAX6 Rebecca Foulger commented on gene: PAX6: DDG2P rating in original PAGE list: Confirmed for KERATITIS HEREDITARY, Confirmed for COLOBOMA OF OPTIC NERVE, Confirmed for PETERS ANOMALY, Confirmed for FOVEAL HYPOPLASIA, Confirmed for BILATERAL OPTIC NERVE HYPOPLASIA, Confirmed for ANIRIDIA and Confirmed for ANIRIDIA CEREBELLAR ATAXIA AND MENTAL DEFICIENCY.
Fetal anomalies v0.3 PAX6 Rebecca Foulger reviewed gene: PAX6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes ANIRIDIA CEREBELLAR ATAXIA AND MENTAL DEFICIENCY for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes ANIRIDIA for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes BILATERAL OPTIC NERVE HYPOPLASIA for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes FOVEAL HYPOPLASIA for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes PETERS ANOMALY for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger Added phenotypes COLOBOMA OF OPTIC NERVE for gene: PAX6
Fetal anomalies v0.1 PAX6 Rebecca Foulger gene: PAX6 was added
gene: PAX6 was added to Fetal anomalies. Sources: Expert Review Green,PAGE DD-Gene2Phenotype
Mode of inheritance for gene: PAX6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: PAX6 were set to KERATITIS HEREDITARY