Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

There was almost a tripling in the risk for NTD in the presence of low maternal B(12) status, measured by holoTC. The benefits of adding synthetic B(12) to current recommendations for periconceptional folic acid tablet supplements or folic-acid-fortified foods need to be considered. It remains to be determined what fraction of NTD cases in a universally folate-fortified environment might be prevented by higher periconceptional intake of B(12).

Hyperphosphatasia with mental retardation syndrome (HPMRS), an autosomal-recessive form of intellectual disability characterized by facial dysmorphism, seizures, brachytelephalangy, and persistent elevated serum alkaline phosphatase (hyperphosphatasia), was recently shown to be caused by mutations in PIGV, a member of the glycosylphosphatidylinositol (GPI)-anchor-synthesis pathway. However, not all individuals with HPMRS harbor mutations in this gene. By exome sequencing, we detected compound-heterozygous mutations in PIGO, a gene coding for a membrane protein of the same molecular pathway, in two siblings with HPMRS, and we then found by Sanger sequencing further mutations in another affected individual; these mutations cosegregated in the investigated families. The mutant transcripts are aberrantly spliced, decrease the membrane stability of the protein, or impair enzyme function such that GPI-anchor synthesis is affected and the level of GPI-anchored substrates localized at the cell surface is reduced. Our data identify PIGO as the second gene associated with HPMRS and suggest that a deficiency in GPI-anchor synthesis is the underlying molecular pathomechanism of HPMRS.

Molecular genetic studies in attention deficit hyperactivity disorder (ADHD) have focussed on candidate genes within the dopamine system, which is thought to be the main site of action of stimulant drugs, the primary pharmacological treatment of the disorder. 1 Of particular interest are findings with the dopamine transporter gene (DAT1), since stimulant drugs interact directly with the transporter protein.2,3 To date, there have been eight published association studies of ADHD with a 480 basepair allele of a variable number tandem repeat (VNTR) polymorphism in the 3Ј-untranslated region of the gene, five 4-8 that support an association and three 9-11 against. We have analysed the same VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children with DSM-IV ADHD, using the transmission disequilibrium test (TDT).12 Results from the UK ( In this study, we have taken a family-based association design to investigate the DAT1 VNTR marker in a dataset of UK Caucasian children and an independent dataset of Turkish Caucasian children. Cases were included if they had a diagnosis of ADHD under DSM-IV criteria and DNA from both parents available for genotyping. They were excluded if they had neurological disease or damage or congenital disorders known to cause hyperactivity. The UK sample consisted of 59 cases with the combined subtype, six the hyperactive/impulsive subtype and one the inattentive subtype of ADHD. Axis 1 co-morbidity other than oppositional defiant disorder and conduct disorder (ODD/CD) consisted of two cases with an affective disorder. The Turkish sample consisted of 111 complete trios with DSM-IV-ADHD combined type. Comorbid diagnoses other than ODD/CD were Tourette's syndrome and/or tics (TS/tics) in 34% and anxiety/depression in 8% of probands.Analysis was performed using the transmission disequilibrium test (TDT) of linkage in the presence of association.12 In order to further evaluate the evidence, we included data from other published reports and performed a combined analysis. The results of this study are shown in Table 1. When considered alone, data from the UK sample ( 2 = 6.12, P = 0.0.01, OR = 1.95), but not the Turkish sample ( 2 = 0.93, P = 0.335), support association and linkage between the DAT1 locus and ADHD.We are not alone in finding differences between datasets. Among previous published reports there have been five providing evidence for the association and three against. The reasons for this are unclear and require further investigation, but may relate to the statistical power of individual samples. To address this issue we combined available published data on the VNTR polymorphism and applied the TDT. Because the TDT is primarily a test of linkage, it is valid to analyse the combined data by adding the number of transmitted and non-transmitted alleles across different studies. As shown in Table 1, combined analysis provides evidence for association and linkage at an alphalevel of 0.06 and odds ratio of 1.15. Although diagnostic differences...

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