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 proband, first of the twins, weighed 2430 g (> 10th centile), the co-twin weighing 2130 g (<10th centile). The most striking features on examination of the proband were macroglossia, moderate sized exomphalos, and widely spaced nipples. No indentation of the ear lobules was noted. Early hypoglycaemia was managed with dextrose infusion, and the exomphalos was corrected within the first 24 hours of life. The second twin was of normal appearance but was small for gestational age. There were no neonatal problems. Examination of the parents did not reveal any ear creases, posterior pits, or divarication of rectus muscles, and they were not of large birthweight.After initial catch up growth the second twin's growth variables at the age of 18 months continued along the 10th centile, and developmental assessment at that age was within normal limits. The proband had feeding difficulties related to her macroglossia, and partial glossectomy was eventually performed at the age of 17 months. Despite these problems her growth has continued along the 50th centile for height, weight, and occipitofrontal head circumference. At the age of 18 months her development was delayed by six months. No abdominal mass was detected at any time.Investigations to determine zygosity showed both twins to be of blood groups A, rr. They were identical when typed for Kell, Fya, Jka, P1, and MNS. In the HLA system both were A 3, 30, B7, 13, and CW 7. The parents were also typed and the final probability of monozygosity was 0 995. Chromosomal preparations were made from cells cultured from peripheral blood of both twins and stained to reveal both C and G bands. No differences were observed in C band polymorphisms, thus supporting monozygosity, and no abnormality was detectable on any chromosome of either child. Chromosome 11 was particularly closely examined on prometaphase cells. Discussion
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