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30-03-2011 | Cardiometabolic | Article

Genetic screening identifies most children with autosomal dominant hypercholesterolemia


Free abstract

MedWire News: Study findings indicate that most of the genes underlying autosomal dominant hypercholesterolemia (ADH) are now known, suggesting that genetic testing can successfully identify the vast majority of children with this condition.

Albert Wiegman (Academic Medical Centre, Amsterdam, The Netherlands) and colleagues report that they were able to identify functional gene mutations in 95% of children with an ADH phenotype.

Furthermore, they say that "previous estimates concerning the percentage of unexplained ADH cases were incorrect," adding that that this was likely due to insufficient clinical assessment of index patients and their relations.

The researchers studied 269 children, aged 4 to 18 years, who were referred to a pediatric clinic in The Netherlands because of dyslipidemia.

All of the chidren had low-density lipoprotein (LDL) cholesterol levels above the 95th percentile for their age and gender, and an autosomal dominant pattern of hypercholesterolemia - indicating an ADH phenotype.

Children with thyroid dysfunction, nephritic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, or obesity (body mass index >75th percentile for age and gender) were excluded from the study, as were those who had been referred to the lipid clinic through a cascade screening program, or if they were from a family with known molecular diagnosis.

The children were screened for mutations in the genes encoding low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9), which are known to underlie ADH.

The team found that only 5% of the group had no identifiable mutation in LDLR, APOB, or PCSK9.

Of the remaining 95% with mutations in these genes, 95% carried a mutation in LDLR and 5% carried a mutation in APOB. No mutations were detected in PCSK9.

Commenting on their findings in the journal Circulation, the researchers say: "In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date."

In an accompanying editorial, Peter Kwiterovich, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, said that this study "re-emphasizes the great importance of detecting children with familial hypercholesterolemia (FH)."

However, knowing how to approach the detection of children with modestly higher LDL cholesterol or obesity, versus those with FH, is currently a major challenge, he remarked.

He concluded that early diagnosis of the condition in childhood through genetic screening methods could lead to the implementation of early and appropriate drug treatment for these high-risk patients.

MedWire ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2011

By Nikki Withers

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