Molecular neonatal screening for homocystinuria in the Qatari population

Abstract

We report the results of molecular neonatal screening for homocystinuria (cystathionine beta-synthase deficiency) in neonates of Qatari origin, developed in conjunction with a novel biochemical screening approach. DNA was extracted from dried blood spots (DBS); the prevalent Qatari CBS gene mutation p.R336C (c.1006C>T) and a second mutation were tested with specific TaqMan assays. Over a period of 2 years we screened 12,603 neonates and identified six affected neonates homozygous for p.R336C. There were 225 heterozygous carriers for p.R336C. One additional child with homocystinuria detected through biochemical screening was homozygous for a mutation not previously identified in Qatar. Homocystinuria in the Qatari population has an incidence of 1:1,800, the highest in the world and even higher than previously estimated. Allele frequency of the mutation p.R336C is approximately 1%, displaying a significant deviation from Hardy Weinberg equilibrium. In conclusion, first-line molecular neonatal screening is technically feasible and may be developed as an option for presymptomatic identification of genetic disorders caused by specific mutations or a limited number of prevalent mutations. However, sensitivity for the diagnosis of disorders caused by various mutations is limited even in a homogeneous population such as Qatar.

Determination of Total Homocysteine, Methylmalonic Acid, and 2-Methylcitric Acid in Dried Blood Spots by Tandem Mass Spectrometry

“…However, as was recently shown for NBS in Qatar (ca. 15000 births per year), where ␤-cystathionine synthase deficiency (Homocystinuria, OMIM ϩ236200) has an incidence of 1 in 1800 live births, a separate measurement of tHCY by a liquid chromatography-tandem mass spectrometry (LC-MS/ MS) method can be affordable and even more effective than molecular genetic testing (7,8 ). In less homogenous and larger populations, this approach cannot be justified, which led several groups, including ours, to develop second-tier methods to improve NBS performance (9,10 ).…”

A Rapid Screening Method for the Measurement of Neonatal Total Homocysteine in Dried Blood Spots by Liquid Chromatography-Tandem Mass Spectrometry

“…NBS programs that include HCU in their disease panel use methionine or tHCY as the primary marker of HCU [5,16,22,23]. The specificity of methionine is poor because it can be increased in other disorders of methionine metabolism, secondary to liver disease, or, most frequently, when neonates receive parenteral nutrition [24].…”

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

“…One limitation is that CBS deficiency in the Qatari population is predominately caused by homozygosity for a frequent mutation (Bener and Hussain 2006;El-Said et al 2006;Zschocke et al 2009;Gan-Schreier et al 2010). Therefore our results are not necessarily transferable to other populations with different genetic backgrounds.…”

“…We previously reported a high prevalence of about 1:3,000 in Qatar. In this highly consanguineous population HCU is caused primarily by homozygosity for the mutation p.R336C (c.1006C>T) in the CBS gene (Bener and Hussain 2006;El-Said et al 2006;Zschocke et al 2009;Gan-Schreier et al 2010).…”