Genetic analysis of strictly defined Leber congenital amaurosis with (and without) neurodevelopmental delay.

Background: Leber congenital amaurosis (LCA) is a severe infantile retinal dystrophy that is non-syndromic other than neurodevelopmental delay, reported in up to 20% of cases according to one older study. The phenotype is typically autosomal recessive and is genetically heterogeneous. Although LCA is defined by a non-recordable electroretinogram (ERG) during infancy, many LCA studies include infants with low ERG readings and/or older children not phenotyped during infancy. More recent series of genetically confirmed LCA do not document the recurrent neurodevelopmental delay of older studies. We investigate the possibility that neurodevelopmental delay is not actually a recurrent feature of strictly defined otherwise non-syndromic LCA.

Methods: Retrospective consecutive case series (2012-2014) of children with strictly defined LCA, all of whom underwent targeted next-generation sequencing with a panel of 14 LCA genes.

Results: All families were endogamous and/or consanguineous. 18/19 (22/23 children) had detectable causative recessive mutations, and these were in one of three genes only: 11 in RPGRIP1, 5 in GUCY2D and 2 in RPE65. 9/11 children with RPGRIP1 mutations harboured homozygous c.1007delA (p.Glu370Asnfs*5) mutation. 5/23 children (22%) had concomitant neurodevelopmental delay, and these five children harboured recessive mutations in RPGRIP1 (2) or GUCY2D (3). Haplotype analysis for cases with the RPGRIP1 deletion suggested a single ancestral mutation.

Conclusions: Neurodevelopmental delay is a potential feature of strictly defined LCA, documented in our series for some children with homozygous RPGRIP1 and GUCY2D mutations. Strictly defining LCA can limit genetic heterogeneity. On the Arabian Peninsula, the phenotype is frequently from recessive RPGRIP1 mutations, most of which are a founder RPGRIP1 deletion.