Objective To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP). Also, to assess genotype-phenotype correlation and disease progression in 10 years by considering type of variants and age of onset. Design Case series. Participants A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD and 75 arRP. Methods Spanish families were analysed through a combination of ABCR400 genotyping microarray, denaturing High-Performance Liquid Chromatography (dHPLC) and High Resolution Melting (HRM) scanning. Direct sequencing was used as confirmation technique for the identified variants. Screening by Multiple Ligation Probe Analysis (MLPA) was used in order to detect possible large deletions or insertions in the ABCA4 gene. Selected families were further analysed by Next Generation Sequencing (NGS). Main Outcome Measures DNA sequence variants, mutation detection rates, haplotypes, age of onset, central or peripheral vision loss, night blindness. Results Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was completely sequenced the detection rates reached 73.6% for STGD and 66.7% for CRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher to that in the general population. Moreover, in some families mutations in other known arRP genes segregated with the disease phenotype. Conclusions An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and is also paramount in selecting patients for emerging clinical trials of therapeutic interventions. As ABCA4-associated diseases are evolving retinal dystrophies, assessment of age of onset, accurate clinical diagnosis and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with an RP-like phenotype often as a consequence of severe (null) mutations and/or in cases of long-term, advanced disease. Patients with “classical” arRP phenotypes, especially from the onset of the disease, should be first screened for mutations in known arRP genes and not ABCA4.

BackgroundPhosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation.MethodsWhole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation.ResultsA novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency.ConclusionsThese results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0190-9) contains supplementary material, which is available to authorized users.