Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

Redin, Claire; Gras, Stéphanie Le; M’Hamdi, Oussama; Geoffroy, Véronique; Stoetzel, Corinne; Vincent, Marie-Claire; Chiurazzi, Pietro; Lacombe, Didier; Ouertani, Inès; Petit, Florence; Till, Marianne; Verloes, Alain; Jost, Bernard; Chaâbouni, Habiba; Dollfus, Hélène; Mandel, Jean‐Louis; Muller, Jean

doi:10.1136/jmedgenet-2012-100875

Cited by 107 publications

(115 citation statements)

References 52 publications

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“…The detection of large variants from NGS data has been shown previously, but its use in FH diagnostics has not yet been investigated. 20,21 Here, the combination of SureSelect Target Enrichment System/ HiSeq and data analysis using ExomeDepth software 18 led to correct identification of all eight large deletions and one large duplication. This shows the potential of using hybrid capture for the detection of both short and large sequence variants in FH.…”

Section: Discussionmentioning

confidence: 99%

The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

Vandrovcová

Thomas

Atanur

et al. 2013

Genetics in Medicine

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Familial hypercholesterolemia (FH, OMIM no. 143890) is a common autosomal dominant condition with a prevalence of 1 in 500. Patients with FH have raised serum cholesterol levels and increased arterial deposition of low-density lipoprotein (LDL) cholesterol, leading to premature coronary heart disease. Despite the fact that early-onset coronary heart disease can be prevented by cholesterol-lowering drugs such as statins, less than a quarter of FH patients have currently been identified in the United Kingdom.1 Several diagnostic criteria have been developed to identify individuals with FH, including the Dutch Lipid Clinic 2 criteria and the MedPed 3 criteria. In the United Kingdom, the clinical diagnosis of FH is based on the Simon Broome criteria of cholesterol levels, presence of tendon xanthomata, family history, and genetic testing. 4 The UK National Institute for Health and Clinical Excellence guidelines recommend initial mutation screening of index cases fulfilling Simon Broome criteria followed by cascade screening in at least firstand second-degree relatives. 5Most cases of FH are caused by mutations in the LDLR gene that encodes the LDL receptor protein, which binds LDL particles at the hepatic cell membrane and internalizes them for processing and excretion. FH-causing mutations in LDLR are found throughout the gene and include missense, truncating, and splice site mutations; small insertion/deletion mutations; and large insertions/deletions that can encompass multiple exons. Some mutations have been found in many unrelated individuals with FH, whereas others are found rarely. 6 Mutations in two other genes, PCSK9 and APOB, can also cause the FH phenotype but in <20% of cases.7 Rare autosomal-recessive hypercholesterolemia is caused by mutations in the LDLRAP1 gene. 8Conventional DNA testing of FH disease-causing genes is mostly based on direct capillary sequencing, with multiplex ligation-dependent probe amplification (MLPA) used for the detection of large insertions or deletions.9 These molecular techniques are sensitive and specific, but because of the cost and time involved, they are impractical for screening large numbers of patients. To overcome some of these limitations, assays such as the Amplification Refractory Mutation System (Elucigene FH20; Tepnel Molecular Diagnostics, Abingdon, UK) or arraybased sequencing methods (LIPOchip; Progenika Biopharma, Derio, Spain) have been developed. These assays are tailored to Purpose: Familial hypercholesterolemia is a common Mendelian disorder associated with early-onset coronary heart disease that can be treated by cholesterol-lowering drugs. The majority of cases in the United Kingdom are currently without a molecular diagnosis, which is partly due to the cost and time associated with standard screening techniques. The main purpose of this study was to test the sensitivity and specificity of two next-generation sequencing protocols for genetic diagnosis of familial hypercholesterolemia. Methods:Libraries were prepared for next-generation sequencing by tw...

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Section: Discussionmentioning

confidence: 99%

The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

Vandrovcová

Thomas

Atanur

et al. 2013

Genetics in Medicine

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“…For this and other rare monogenic diabetes syndromes, the use of systematic genetic diagnosis may reveal the true prevalence and extent of variability of this and clinically overlapping syndromes. 24 This would be particularly important to consider in populations where the prevalence of consanguinity or endogamy is high.…”

Section: Discussionmentioning

confidence: 99%

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

et al. 2013

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Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alströ m syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T4G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alströ m syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

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“…DNA library preparation, enrichment (SureSelect, Agilent Technologies, Santa Clara, CA, USA) and sequencing (HiSeq2500, Illumina) were performed as previously described. 37 Pedigree concordance was checked using highly polymorphic microsatellite markers (PowerPlex 16 HS System, Promega, Madison, WI, USA).…”

Section: Methodsmentioning

confidence: 99%

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

et al. 2015

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The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

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Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström Syndromes

Cited by 107 publications

References 52 publications

The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient

Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

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