The Δ&gt;15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction‐based diagnostic assay and prevalence in Quebec

Simard, Louise R.; Viel, J; Lambert, Marie; Paradis, Gilles; Lévy, Émile; Delvin, EE; Mitchell, G. H.

doi:10.1111/j.0009-9163.2004.00223.x

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…We used the reported method to detect ⌬Ͼ 15 kb in these five patients (13). We first found that each had the diagnostic 435 bp band that could only be amplified if the deletion was present (13), that each was heterozygous for this mutant fragment, and that the sequence of this fragment corresponded to ⌬Ͼ 15 kb (13) in all five subjects ( Fig. 3 ).…”

Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

“…All of these patients had French surnames, leading us to consider that this particular MLPA pattern might have resulted from the Ͼ 15 kb deletion ( ⌬Ͼ 15 kb) at the 5 Ј end of the LDLR . This deletion is the most common cause of FH in French Canadians (1,13). We used the reported method (13) to sequence the deletion break points in these five patients.…”

Section: Dna Sequence Confirmation Of Deletion Break Pointmentioning

confidence: 99%

“…This deletion is the most common cause of FH in French Canadians (1,13). We used the reported method (13) to sequence the deletion break points in these five patients. Briefly, primer pairs 23F (5 Ј -CAC ATG CTC GAG TGT AAG AAC-3 Ј ) and 17R (5 Ј -GGT TGG CGT TTT TCA TAT TAG ACC-3 Ј ) were used to amplify a 435 bp fragment spanning the deletion break point.…”

Section: Dna Sequence Confirmation Of Deletion Break Pointmentioning

confidence: 99%

“…We noted that the five subjects with the MLPA pattern corresponding to ⌬ exon 1 each had French surnames. This led us to consider that this abnormal MLPA pattern might have been the result of the ⌬Ͼ 15 kb deletion at the 5 Ј end of the LDLR that is the most prevalent cause of FH in FrenchCanadian patients (13). We used the reported method to detect ⌬Ͼ 15 kb in these five patients (13).…”

Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

“…This led us to consider that this abnormal MLPA pattern might have been the result of the ⌬Ͼ 15 kb deletion at the 5 Ј end of the LDLR that is the most prevalent cause of FH in FrenchCanadian patients (13). We used the reported method to detect ⌬Ͼ 15 kb in these five patients (13). We first found that each had the diagnostic 435 bp band that could only be amplified if the deletion was present (13), that each was heterozygous for this mutant fragment, and that the sequence of this fragment corresponded to ⌬Ͼ 15 kb (13) in all five subjects ( Fig.…”

Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

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Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Wang

Ban

Hegele

2005

Journal of Lipid Research

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Autosomal dominant (AD) familial hypercholesterolemia [FH; Mendelian Inheritance in Man (MIM) 143890]typically results from mutations in the LDL receptor gene ( LDLR ), which are now commonly diagnosed using exon-byexon screening methods, such as exon-by-exon sequence analysis (EBESA) of genomic DNA (gDNA). However, many patients with FH have no LDLR mutation identified by this method. Part of the diagnostic gap is attributable to the genetic heterogeneity of AD FH, but another possible explanation is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR . Affected individuals have increased plasma LDL cholesterol, which without adequate diagnosis and intervention can increase the risk of fatal coronary heart disease by up to 100-fold compared with the general population (2).Fortunately, treatment with statin drugs can substantially reduce this risk and improve clinical outcome (2), stressing the importance of early and accurate diagnosis.At the molecular level, FH is now commonly diagnosed using exon-by-exon screening methods, such as exon-byexon sequence analysis (EBESA) of LDLR from genomic DNA (gDNA) (3, 4). However, this method finds mutations in only ‫ف‬ 50% of clinically diagnosed FH patents (3, 4). Part of the diagnostic gap is attributable to the heterogeneity of AD FH (5). For instance, HCHOLAD2 (MIM 144010), which results from a missense mutation in APOB affecting the LDL receptor binding domain of apolipoprotein B-100 (apoB-100; MIM 107730) (6, 7), accounts for 5-10% of the AD FH phenotype. A rare FH subtype called HCHOLAD3 (MIM 603776) results from mutations in PCSK9 (MIM 607786), encoding neural apoptosis-regulated convertase-1 (5, 8, 9). A similarly rare autosomal recessive FH subtype called HCHOLAR1 (MIM 603813) results from mutations in ARH (MIM 605747), encoding a putative adaptor for the LDL receptor (10). However, even after accounting for genetic heterogeneity, many clinically diagnosed FH patients have no LDLR mutation with EBESA.Another possible explanation for the gap in FH molecular diagnosis is inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions. The larger gDNA alterations create effective hemizygosity for single exons and result in an EBESA profile that is indistinguishable from homozygosity for two normal LDLR alleles. Multiplex ligation-dependent probe amplification (MLPA) is a new analytical method (11) that detects larger gDNA deletions or insertions that would otherwise be overlooked by EBESA (12). We hypothesized that some FH patients with no LDLR mutation detectable by EBESA would have an abnormality detectable using MLPA. Of 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splic-

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Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

Section: Dna Sequence Confirmation Of Deletion Break Pointmentioning

confidence: 99%

Section: Dna Sequence Confirmation Of Deletion Break Pointmentioning

confidence: 99%

Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

Section: Dna Sequence Break Point Confirmation In Fh Patients With Abmentioning

confidence: 99%

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Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Wang

Ban

Hegele

2005

Journal of Lipid Research

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Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis

Wong

Levy‐Sakin

et al. 2019

Molec Gen & Gen Med

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BackgroundHomozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low‐density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.ObjectiveWe aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.MethodsWe applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked‐Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR‐based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL.ResultsIn the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs.ConclusionsWhile the application of WES can provide a cost‐effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked‐Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES.

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Decreased dystrophin expression and elevated dystrophin-targeting miRNAs in anti-HMGCR immune-mediated necrotizing myopathy

Marmen,

Orfi,

Dort

et al. 2023

Acta Neuropathol

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The Δ>15 Kb deletion French Canadian founder mutation in familial hypercholesterolemia: rapid polymerase chain reaction‐based diagnostic assay and prevalence in Quebec

Cited by 17 publications

References 21 publications

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia

Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis

Decreased dystrophin expression and elevated dystrophin-targeting miRNAs in anti-HMGCR immune-mediated necrotizing myopathy

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