High-Resolution Homozygosity Mapping Is a Powerful Tool to Detect Novel Mutations Causative of Autosomal Recessive RP in the Dutch Population

Collin, Rob W.J.; Born, L. Ingeborgh van den; Klevering, B. Jeroen; Castro-Miró, Marta de; Littink, Karin W.; Arimadyo, Kentar; Azam, Maleeha; Yazar, Volkan; Zonneveld, Marijke N.; Păun, C.; Siemiątkowska, Anna; Strom, Tim M.; Hehir-Kwa, Jayne Y.; Kroes, Hester Y.; Faber, Jan Tjeerd de; Schooneveld, Mary J. van; Heckenlively, John R.; Hoyng, Carel B.; Hollander, Anneke I. den; Cremers, Frans P.M.

doi:10.1167/iovs.10-6185

Cited by 67 publications

(64 citation statements)

References 81 publications

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“…[27][28][29] In one of these studies, identification of homozygosity regions and further sequencing of LCA genes within these regions resulted in detection of 10 homozygous mutations, 7 of which were novel. 27 LCA genes CEP290 and LCA5 were identified by the same approach.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C4T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T4C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773 þ 3A4G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…We and others have shown that the autozygome approach can be very effective in guiding the mutation analysis (Aldahmesh et al 2009;Pomares et al 2010). Interestingly, this approach was also used successfully in populations where consanguinity is uncommon (Hildebrandt et al 2009;Collin et al 2011;Hagiwara et al 2011;Schuurs-Hoeijmakers et al 2011). However, this approach has its limitations.…”

Section: Autozygome/exome Analysis In Retinal Dystrophymentioning

confidence: 99%

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

et al. 2012

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Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.

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“…Panels of 300-400 microsatellite markers, equally distributed across the genome with a resolution of approximately 10 Mb (average spacing) genome-wide, were used widely [87] . This method has been successful in large consanguineous families to identify ROH that encompassed the respective genetic defect [88] . However, the resolution is too low to study small non-consanguineous families [88] .…”

Section: High-resolution Genotyping Techniquesmentioning

confidence: 99%

“…This method has been successful in large consanguineous families to identify ROH that encompassed the respective genetic defect [88] . However, the resolution is too low to study small non-consanguineous families [88] . Only some ten years ago, high throughput and robust microarray-based SNP genotyping was introduced, which has the additional advantage that they are also highly powerful in the detection of CNVs [89] .…”

Section: High-resolution Genotyping Techniquesmentioning

confidence: 99%

Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

Iqbal

Bokhoven

2014

Hum Hered

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Consanguinity is an important determinant of birth defects including intellectual disability (ID). Consanguineous populations have a relative high prevalence of autosomal recessive forms of intellectual disability (ARID), which constitute a highly heterogeneous group of disorders both in their clinical presentation and in their genetic aetiology. The availability of large cohorts of consanguineous families and the advent of next-generation sequencing techniques is currently accelerating the pace of gene identification in ARID. Because of the extreme heterogeneity, it is anticipated that hundreds of ARID (candidate) genes will be identified in the near future. With this robust progress, the proof of causality of the identified candidate genes is challenging. To this end, genetic recurrence, cellular assays and animal modelling would serve as three non-exclusive strategies, in order to assign causality to a certain gene. Extensive genetic investigations in consanguineous populations will help in reducing the total disease burden through proper genetic counselling. Moreover, such findings will be helpful to elucidate different pathways and further for possible therapeutic interventions.

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High-Resolution Homozygosity Mapping Is a Powerful Tool to Detect Novel Mutations Causative of Autosomal Recessive RP in the Dutch Population

Abstract: This report demonstrates that homozygosity mapping is a powerful tool for identifying the genetic defect underlying genetically heterogeneous recessive disorders like RP, even in populations with little consanguinity.

Cited by 67 publications

References 81 publications

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

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

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

Identifying Genes Responsible for Intellectual Disability in Consanguineous Families

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