A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents

Wierenga, Klaas J.; Jiang, Zhijie; Yang, Amy; Mulvihill, John J.; Tsinoremas, Nicholas F.

doi:10.1038/gim.2012.136

Cited by 55 publications

(58 citation statements)

References 13 publications

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“…Homozygous areas 475 Mb and segregating only with the proband were examined using the online software, Genomic Oligoarray and a SNP array evaluation tool; candidate genes were selected using an autosomal recessive model filter. 9 For Sanger dideoxy sequencing, primers were designed to cover all coding exons and flanking intronic regions of DGAT1 (NM_012079.5; primer sequences available upon request). Direct sequencing of PCR amplification products was performed using BigDye 3.1 Terminator Chemistry (Applied Biosystems, Woolston, Warrington, UK); products were separated on an ABI 3130xl genetic analyzer (Applied Biosystems, Foster City, CA, USA).…”

Section: Homozygosity Mapping and Sequencingmentioning

confidence: 99%

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

et al. 2016

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Protein-losing enteropathy (PLE) is a clinical disorder of protein loss from the gastrointestinal system that results in hypoproteinemia and malnutrition. This condition is associated with a wide range of gastrointestinal disorders. Recently, a unique syndrome of congenital PLE associated with biallelic mutations in the DGAT1 gene has been reported in a single family. We hypothesize that mutations in this gene are responsible for undiagnosed cases of PLE in infancy. Here we investigated three children in two families presenting with severe diarrhea, hypoalbuminemia and PLE, using clinical studies, homozygosity mapping, and exome sequencing. In one family, homozygosity mapping using SNP arrays revealed the DGAT1 gene as the best candidate gene for the proband. Sequencing of all the exons including flanking regions and promoter regions of the gene identified a novel homozygous missense variant, p.(Leu295Pro), in the highly conserved membrane-bound O-acyl transferase (MBOAT) domain of the DGAT1 protein. Expression studies verified reduced amounts of DGAT1 in patient fibroblasts. In a second family, exome sequencing identified a previously reported splice site mutation in intron 8. These cases of DGAT1 deficiency extend the molecular and phenotypic spectrum of PLE, suggesting a re-evaluation of the use of DGAT1 inhibitors for metabolic disorders including obesity and diabetes.

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Section: Homozygosity Mapping and Sequencingmentioning

confidence: 99%

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

et al. 2016

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“…Gene content and phenotype associations for ROH segments were evaluated by utilizing the web-based Genomic Oligoarray and SNP array evaluation tool, developed and made available by Wierenga et al 12 By entering the genomic coordinates of all ROHs in this tool (www.ccs.miami.edu/ROH), a list of the OMIM genes mapping to those particular regions, and their associated (recessive) disorders, was generated for review. 12 …”

Section: Searching For Potential Candidate Genes In Rohs For Autosomamentioning

confidence: 99%

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

et al. 2014

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Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso-and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso-and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader-Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.

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“…Percent autosomal homozygosity was calculated using long contiguous stretches of homozygousity (LCSH) at least 3.0 Mb in size. Autozygosity mapping to identify recessive disorder genes was performed with the Genomic Oligoarray and SNP array evaluation tool v2.0 [10] .…”

Section: Genetic Testingmentioning

confidence: 99%

Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

Turner

Dinulos

Vallee

et al. 2015

CRCP

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Objective: Lack of newborn screening, limited access to healthcare, and complex presentation has resulted in gross under-diagnosis of in-born metabolism disorders in many Central American countries. In this study we describe the use of advanced clinical genomics to identify a novel cystathionine-beta-synthase (CBS) mutation with limited clinical information from a small highly consanguineous indigenous community in rural Honduras. Methods:We performed chromosomal microarray analysis and whole exome sequencing on three affected siblings and their mother. Confirmatory Sanger sequencing for CBS exon 10 was performed on genomic DNA from extended family within the community. Results:We identified a novel homozygous missense mutation (p.Tyr308Thrfs*11) in CBS that resulted in the diagnosis of homocystinuria in three siblings. Patients were nonresponsive to standard pyridoxine treatment. We discovered an elevated coefficient of inbreeding (F ≥ 0.20) suggestive of an unreported highly consanguineous population. Genotyping identified ~47% of extended family as carriers of this novel mutation. Conclusion:Expanded use of whole exome sequencing from buccal cell genomic DNA allowed for the discovery of a novel mutation resulting in a rare recessive disorder in an isolated under-served population. Clinical phenotypes and treatment response of patients with this novel homozygous mutation add to our clinical understanding of homocystinuria.

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A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents

Cited by 55 publications

References 13 publications

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations

Regions of homozygosity identified by oligonucleotide SNP arrays: evaluating the incidence and clinical utility

Discovery of a novel cystathionine-beta-synthase mutation and diagnosis of homocystinuria by whole exome sequencing in a family from rural Honduras

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