Leber congenital amaurosis: Comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis

Abstract

Communicated by Jean-Claude KaplanLeber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies, responsible for congenital blindness. Disease-associated mutations have been hitherto reported in seven genes. These genes are all expressed preferentially in the photoreceptor cells or the retinal pigment epithelium but they are involved in strikingly different physiologic pathways resulting in an unforeseeable physiopathologic variety. This wide genetic and physiologic heterogeneity that could largely increase in the coming years, hinders the molecular diagnosis in LCA patients. The genotyping is, however, required to establish genetically defined subgroups of patients ready for therapy. Here, we report a comprehensive mutational analysis of the all known genes in 179 unrelated LCA patients, including 52 familial and 127 sporadic (27/127 consanguineous) cases. Mutations were identified in 47.5% patients. GUCY2D appeared to account for most LCA cases of our series (21.2%), followed by CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%). The clinical history of all patients with mutations was carefully revisited to search for phenotype variations. Sound genotype-phenotype correlations were found that allowed us to divide patients into two main groups. The first one includes patients whose symptoms fit the traditional definition of LCA, i.e., congenital or very early cone-rod dystrophy, while the second group gathers patients affected with severe yet progressive rodcone dystrophy. Besides, objective ophthalmologic data allowed us to subdivide each group into two subtypes. Based on these findings, we have drawn decisional flowcharts directing the molecular analysis of LCA genes in a given case. These flowcharts will hopefully lighten the heavy task of genotyping new patients but only if one has access to the most precise clinical history since birth.

Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA

“…It is obvious that there are still unidentified mutations in LCA and further genetic mapping and cloning of new candidate genes are required. 9 In another genetic study, 17 a homozygous nonsense mutation, Trp278X, in the photoreceptor-pineal gene AIPL1 was found in four Pakistani families with LCA. These patients presented with a severe phenotype of LCA with hand motion to no light perception vision and fundus findings ranging from maculopathy to diffuse pigmentary retinopathy.…”

“…In the series of Perrault et al, 16 GUCY2D, RPE65, and CRX genes accounted for 27% of Leber cases. Hanein et al, 9 screened seven LCA causative genes in 179 unrelated LCA cases and found mutations in 47.5% of the patients (GUCY2D (21.2%), CRB1 (10%), RPE65 (6.1%), RPGRIP1 (4.5%), AIPL1 (3.4%), TULP1 (1.7%), and CRX (0.6%)). It is obvious that there are still unidentified mutations in LCA and further genetic mapping and cloning of new candidate genes are required.…”

“…It can also present with bull's eye-type macular changes and macular coloboma-like lesions. 1 Genetic defects in GUCY2D (retinal guanylate cyclase, 17p13.1), 2 AIPL1 (aryl hydrocarbon receptor-interacting protein-like 1, 17p13.2), 3 CRB1 (Crumbs homolog 1, 1q31.3), 4 CRX (photoreceptor specific cone-rod homeobox transcription factor, 19q13.32), 5 RPE65 (retinal pigment epithelium specific 65 kDa protein, 1p31.2), 6 RPGRIP1 (retinitis pigmentosa GTPase regulator-interacting protein 1, 14q11.2), 7 RDH12 (retinal dehydrogenase 12, 14q24.1) 8 and TULP1 (Tubby-like protein 1, 6p21.31) 9 have been associated with LCA. Additionally, three independent loci with unidentified genes, LCA3 (14q24), 10 LCA5 (6q11-q16), 11 and LCA9 (1p36) 12 have been found to show linkage to LCA.…”

Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families

“…Today, 24 pathogenic variants have been described in TULP1, including 12 missense and 12 nonsense or frameshift mutations. [17][18][19][20][21][22][23][24][25][26][27] In all, 10 out of the 12 missense mutations are present in the tubby domain. The two novel missense mutations, R311Q and R342Q, that we have found in this study also affect amino acids of the tubby domain.…”

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

“…The following genes are known to be associated with LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, CEP290, IMPDH1, RD3, RDH12, KCNJ13, LRAT and TULP1. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is difficult to estimate the proportion of patients with mutations in the different genes, as some, such as IMPDH1 (LCA11) is considered to be rare, other, as CEP290 accounts for almost 20%, and for some such as TULP1 and LRAT the number is uncertain. One of the most studied LCA genes is CRB1 at 1q31q32.1, which consists of 12 exons and encodes a protein Crumbs homologue that participates in determination and maintenance of photoreceptor architecture.…”