Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping

Harville, Heather M.; Held, Susanne; Dı́az-Font, Anna; Davis, Erica E.; Diplas, Bill H.; Lewis, Richard A.; Borochowitz, Zvi; Zhou, Weibin; Chaki, Moumita; MacDonald, J.; Kayserili, Hülya; Beales, Philip L.; Katsanis, Nicholas; Otto, Edgar A.; Hildebrandt, Friedhelm

doi:10.1136/jmg.2009.071365

Cited by 64 publications

(59 citation statements)

References 30 publications

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“…Homozygosity-mapping, on the other hand, is a more powerful and effective approach to study recessive disorders in consanguineous families (Harville et al 2010;Pang et al 2010;Iseri et al 2010;Collin et al 2010). For those disorders that are not amendable to these two conventional approaches, their causal variants remain elusive.…”

Section: Introductionmentioning

confidence: 97%

Revisiting Mendelian disorders through exome sequencing

2011

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Over the past several years, more focus has been placed on dissecting the genetic basis of complex diseases and traits through genome-wide association studies. In contrast, Mendelian disorders have received little attention mainly due to the lack of newer and more powerful methods to study these disorders. Linkage studies have previously been the main tool to elucidate the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not amendable to this study design. Exome sequencing has now become technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies which have offered new opportunities for Mendelian disorder research. Exome sequencing has been swiftly applied to the discovery of new causal variants and candidate genes for a number of Mendelian disorders such as Kabuki syndrome, Miller syndrome and Fowler syndrome. In addition, de novo variants were also identified for sporadic cases, which would have not been possible without exome sequencing. Although exome sequencing has been proven to be a promising approach to study Mendelian disorders, several shortcomings of this method must be noted, such as the inability to capture regulatory or evolutionary conserved sequences in non-coding regions and the incomplete capturing of all exons.

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Section: Introductionmentioning

confidence: 97%

Revisiting Mendelian disorders through exome sequencing

2011

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“…Mutations in selected known NPHP-related condition genes were excluded using an approach of highthroughput mutation analysis. 33,34 Homozygosity Mapping…”

Section: Research Participantsmentioning

confidence: 99%

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Hurd

Otto

Mishima

et al. 2013

Journal of the American Society of Nephrology

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Nephronophthisis (NPHP)-related ciliopathies are recessive, single-gene disorders that collectively make up the most common genetic cause of CKD in the first three decades of life. Mutations in 1 of the 15 known NPHP genes explain less than half of all cases with this phenotype, however, and the recently identified genetic causes are exceedingly rare. As a result, a strategy to identify single-gene causes of NPHP-related ciliopathies in single affected families is needed. Although whole-exome resequencing facilitates the identification of disease genes, the large number of detected genetic variants hampers its use. Here, we overcome this limitation by combining homozygosity mapping with whole-exome resequencing in a sibling pair with an NPHP-related ciliopathy. Whole-exome capture revealed a homozygous splice acceptor site mutation (c.698G.T) in the renal Mg 2+ transporter SLC41A1. This mutation resulted in skipping of exon 6 of SLC41A1, resulting in an in-frame deletion of a transmembrane helix. Transfection of cells with wild-type or mutant SLC41A1 revealed that deletion of exon 6 completely blocks the Mg 2+ transport function of SLC41A1. Furthermore, in normal human kidney tissue, endogenous SLC41A1 specifically localized to renal tubules situated at the corticomedullary boundary, consistent with the region of cystogenesis observed in NPHP and related ciliopathies. Last, morpholino-mediated knockdown of slc41a1 expression in zebrafish resulted in ventral body curvature, hydrocephalus, and cystic kidneys, similar to the effects of knocking down other NPHP genes. Taken together, these data suggest that defects in the maintenance of renal Mg 2+ homeostasis may lead to tubular defects that result in a phenotype similar to NPHP.

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“…This approach has been shown to be powerful and is particularly useful in investigating autosomal recessive disorders especially in populations with a high prevalence of consanguinity. This is evident from the enormous number of studies identifying causal mutations for autosomal recessive disorders in consanguineous families (Abu SaWeh et al 2010;Harville et al 2010;Walsh et al 2010;Pang et al 2010;Lapunzina et al 2010;Nicolas et al 2010;Uz et al 2010;Iseri et al 2010;Collin et al 2010). However, the Wrst study applying the homozygosity association approach at the genome-wide scale for complex diseases only appeared in 2007 (Lencz et al 2007).…”

Section: Implications On Complex Diseases and Traitsmentioning

confidence: 94%

Regions of homozygosity and their impact on complex diseases and traits

Naidoo

Teo

et al. 2010

Hum Genet

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Regions of homozygosity (ROHs) are more abundant in the human genome than previously thought. These regions are without heterozygosity, i.e. all the genetic variations within the regions have two identical alleles. At present there are no standardized criteria for defining the ROHs resulting in the different studies using their own criteria in the analysis of homozygosity. Compared to the era of genotyping microsatellite markers, the advent of high-density single nucleotide polymorphism genotyping arrays has provided an unparalleled opportunity to comprehensively detect these regions in the whole genome in different populations. Several studies have identified ROHs which were associated with complex phenotypes such as schizophrenia, late-onset of Alzheimer's disease and height. Collectively, these studies have conclusively shown the abundance of ROHs larger than 1 Mb in outbred populations. The homozygosity association approach holds great promise in identifying genetic susceptibility loci harboring recessive variants for complex diseases and traits.

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Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping

Cited by 64 publications

References 30 publications

Revisiting Mendelian disorders through exome sequencing

Revisiting Mendelian disorders through exome sequencing

Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Regions of homozygosity and their impact on complex diseases and traits

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