Genetic Analysis of ‘PAX6-Negative’ Individuals with Aniridia or Gillespie Syndrome

Abstract

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3ʹ (telomeric) to PAX6 and one within a gene desert 5ʹ (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated.

The clinical evaluation of infantile nystagmus: What to do first and why

“…Other signs of a primarily neurologic disorder may be unusual nystagmus such as see-saw or spasmus nutans (shimmering and asymmetric) (4,5), co-occurrence of ocular motor apraxia (6), ataxia, pale or small optic nerves, or swollen optic nerves. Chorioretinal colobomas may also be associated with midline brain defects, while iris-only colobomas, when in an unusual position away from the inferonasal region, may signify Gillespie syndrome due to mutations in PAX6 or other genes (7,8). Small optic nerves may be due to primary optic nerve hypoplasia (ONH), with or without abnormalities of the septum pellucidum, pituitary gland and posterior pituitary bright spot.…”

The clinical evaluation of infantile nystagmus: what to do first, and why

“…Other signs of a primarily neurologic disorder may be unusual nystagmus such as see-saw or spasmus nutans (shimmering and asymmetric) (4,5), co-occurrence of ocular motor apraxia (6), ataxia, pale or small optic nerves, or swollen optic nerves. Chorioretinal colobomas may also be associated with midline brain defects, while iris-only colobomas, when in an unusual position away from the inferonasal region, may signify Gillespie syndrome due to mutations in PAX6 or other genes (7,8). Small optic nerves may be due to primary optic nerve hypoplasia (ONH), with or without abnormalities of the septum pellucidum, pituitary gland and posterior pituitary bright spot.…”

PAX6 allelic heterogeneity in Mexican congenital aniridia patients: expanding the mutational spectrum with seven novel pathogenic variants

“…In addition, they identified six deletions within plausible cis ‑regulatory effects (five of them on 3′ telomeric PAX6 region and one within a 5′ telomeric PITX2 sequence ) and two missense mutations in FOXC1 . Thus, locus heterogeneity may exist in isolated aniridia . Recently, a mutation was reported in a cis –element 150 Kb downstream from PAX6 which results in defective maintenance of PAX6 expression, thus demonstrating variants in a regulatory sequence in an affected individual with an intact PAX6 coding region …”

“…Thus, locus heterogeneity may exist in isolated aniridia. 31 Recently, a mutation was reported in a cis-element 150 Kb downstream from PAX6 which results in defective maintenance of PAX6 expression, thus demonstrating variants in a regulatory sequence in an affected individual with an intact PAX6 coding region. 32 Loss of function of one PAX6 allele (i.e.…”