Browsing by Author "Van Esch, H"
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- Genetic Screening of LCA in Belgium: Predominance of CEP290 and Identification of Potential Modifier Alleles in AHI1 of CEP290-Related PhenotypesPublication . Coppieters, F; Casteels, I; Meire, F; De Jaegere, S; Hooghe, S; van Regemorter, N; Van Esch, H; Matuleviciene, A; Nunes, L; Meersschaut, V; Walraedt, S; Standaert, L; Coucke, P; Hoeben, H; Kroes, H; Vande Walle, J; de Ravel, T; Leroy, B; De Baere, ELeber Congenital Amaurosis (LCA), the most severe inherited retinal dystrophy, is genetically heterogeneous, with 14 genes accounting for 70% of patients. Here, 91 LCA probands underwent LCA chip analysis and subsequent sequencing of 6 genes (CEP290, CRB1, RPE65, GUCY2D, AIPL1and CRX), revealing mutations in 69% of the cohort, with major involvement of CEP290 (30%). In addition, 11 patients with early-onset retinal dystrophy (EORD) and 13 patients with Senior-Loken syndrome (SLS), LCA-Joubert syndrome (LCA-JS) or cerebello-oculo-renal syndrome (CORS) were included. Exhaustive re-inspection of the overall phenotypes in our LCA cohort revealed novel insights mainly regarding the CEP290-related phenotype. The AHI1 gene was screened as a candidate modifier gene in three patients with the same CEP290 genotype but different neurological involvement. Interestingly, a heterozygous novel AHI1 mutation, p.Asn811Lys, was found in the most severely affected patient. Moreover, AHI1 screening in five other patients with CEP290-related disease and neurological involvement revealed a second novel missense variant, p.His758Pro, in one LCA patient with mild mental retardation and autism. These two AHI1 mutations might thus represent neurological modifiers of CEP290-related disease.
- The Role of AKT3 Copy Number Changes in Brain Abnormalities and Neurodevelopmental Disorders: Four New Cases and Literature ReviewPublication . Lopes, F; Torres, F; Soares, G; van Karnebeek, CD; Martins, C; Antunes, D; Silva, J; Muttucomaroe, L; Botelho, LF; Sousa, S; Rendeiro, P; Tavares, P; Van Esch, H; Rajcan-Separovic, E; Maciel, PMicrodeletions at 1q43-q44 have been described as resulting in a clinically recognizable phenotype of intellectual disability (ID), facial dysmorphisms and microcephaly (MIC). In contrast, the reciprocal microduplications of 1q43-q44 region have been less frequently reported and patients showed a variable phenotype, including macrocephaly. Reports of a large number of patients with copy number variations involving this region highlighted the AKT3 gene as a likely key player in head size anomalies. We report four novel patients with copy number variations in the 1q43-q44 region: one with a larger deletion (3.7Mb), two with smaller deletions affecting AKT3 and SDCCAG8 genes (0.16 and 0.18Mb) and one with a quadruplication (1Mb) that affects the entire AKT3 gene. All patients with deletions presented MIC without structural brain abnormalities, whereas the patient with quadruplication had macrocephaly, but his carrier father had normal head circumference. Our report also includes a comparison of phenotypes in cases with 1q43-q44 duplications to assist future genotype-phenotype correlations. Our observations implicate AKT3 as a contributor to ID/development delay (DD) and head size but raise doubts about its straightforward impact on the latter aspect of the phenotype in patients with 1q43-q44 deletion/duplication syndrome.