Search

Intellectual disability ( ID) is an unresolved health care problem with a worldwide prevalence rate of 2-3%. For many years, research into the genetic causes of ID and related disorders has mainly focused on chromosomal abnormalities or X-linked genetic deficits. Only a handful of autosomal genes are known to cause ID. At the same time it has been suggested that at least some cases of ID represent an extreme form of normal intellectual ability and therefore that genes important for intellectual ability in the normal range may also play a role in ID. In this study, we tested whether the autosomal SNAP25 gene, which was previously associated with variation in intellectual ability in the normal range, is also associated with ID. The gene product of SNAP25 is an important presynaptic plasma membrane protein, is known to be involved in regulating neurotransmitter release, and has been linked to memory and learning by its effect on long term potentiation in the hippocampus. Allele frequencies of two genetic variants in SNAP25 previously associated with intellectual ability were compared between a group of 636 ID cases ( IQ < 70) and a control group of 361 persons of higher than average intellectual ability. We observed a higher frequency of the putative risk allele of rs363050 ( P = 0.02; OR = 1.24) in cases as compared to controls. These results are consistent with a role of SNAP25 in ID, and also support the notion that ID reflects the lower extreme of the quantitative distribution of intellectual ability. [ABSTRACT FROM AUTHOR]

Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic effect of the deletion of both genes would explain the condition. Subsequently, however, a patient with a larger 10q23 deletion including the same genes but with a mild clinical phenotype was identified. Here, we present four additional patients with 10q23 microdeletions involving the PTEN and BMPR1A genes. The sizes of the deletions were analyzed using single nucleotide polymorphism array analysis. All patients had macrocephaly, dysmorphic features, retardation and congenital abnormalities. One patient developed colorectal cancer. However, only one case had disease onset before 2 years of age and severe symptoms requiring colectomy. No clear correlation was found between ages at onset or severity of gastrointestinal symptoms and the sizes of the deletions. We conclude that patients with 10q23 microdeletions involving the PTEN and BMPR1A genes have variable clinical phenotypes, which cannot be explained merely by the deletion sizes. The phenotypes are not restricted to severe infantile juvenile polyposis but include childhood-onset cases with macrocephaly, retardation, mild gastrointestinal symptoms and possibly early-onset colorectal cancer. [ABSTRACT FROM AUTHOR]

Submicroscopic subtelomeric aberrations are a common cause of mental retardation (MR). New molecular techniques allow the identification of subtelomeric microduplications, but their frequency and significance are largely unknown. We determined the frequency of subtelomeric, pure microduplications in a cohort of 624 patients with MR and/or multiple congenital anomalies using multiplex ligation dependent probe amplification (MLPA) and delineated the identified microduplications using array based comparative genomic hybridization (array CGH). In 11 patients, MLPA revealed a subtelomeric duplication without a concurrent deletion. Additional fluorescence in situ hybridization studies and parental analyses showed that three had occurred de novo: one duplication 5q34qter (12.7 Mb), one duplication 9q34.13qter (7.2 Mb) and one duplication 9p24.2pter (4.1 Mb). Five microduplications (9p, 11q, 12q, 15q and 16p) appeared to be inherited from an unaffected parent, while in three cases (9p, 12p and 17p) the parents were not available for testing. Based on our findings and data from the literature, the three de novo duplications were the only ones likely to be disease-causing, leading to a frequency of pathogenic subtelomeric, pure microduplications of 0.5%. Our study shows that subtelomeric microduplications are an infrequent cause of MR and that additional clinical and family studies are required to assess their clinical significance. [ABSTRACT FROM AUTHOR]

The field of prenatal screening has rapidly changed as a result of the introduction of cell-free DNA (cfDNA) testing[[1]]. cfDNA testing can be offered as targeted analysis for the three common trisomies or as genome-wide (GW) analysis. Finally, Jani I et al i .[3] raise concerns regarding parental counseling and termination of pregnancy after additional findings on GW-cfDNA testing. [Extracted from the article]

Kleefstra T, Franken CE, Arens YHJM, Ramakers GJA, Yntema HG, Sistermans EA, Hulsmans CFCH, Nillesen WN, van Bokhoven H, de Vries BBA, Hamel BCJ. Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1).Recently, the polyglutamine-binding protein 1 (PQBP1) gene was found to be mutated in five of 29 families studied with X-linked mental retardation (XLMR) linked to Xp. The reported mutations include duplications or deletions of AG dinucleotides in the fourth coding exon that resulted in shifts of the open reading frame. Three of the five families with mutations in this newly identifiedXLMRgene have been reported previously. We characterized the phenotypic and neuropsychological features in the two unpublished families with aberrations inPQBP1and in a family reported 10 years ago. In total, seven patients diagnosed with aberrations in this gene were examined, including a newly identified patient at 18 months of age. Additionally, the features were compared to those reported in the literature of three other families, comprising MRXS3 (Sutherland–Haan syndrome) MRX55 and MRXS8 (Renpenning syndrome). Characteristics seen in these patients are microcephaly, lean body habitus, short stature, striking facial appearance with long narrow faces, upward slant of the eyes, malar hypoplasia, prognathism, high-arched palate and nasal speech. In addition, small testes and midline defects as anal atresia or imperforate anus, clefting of palate and/or uvula, iris coloboma and Tetralogy of Fallot are seen in several patients. These observations contribute to the phenotypic knowledge of patients withPQBP1mutations and make this XLMR syndrome well recognizable to clinicians. [ABSTRACT FROM AUTHOR]

Follow-up investigations were undertaken on a previously reported patient who had severe familial giant cell hepatitis in infancy associated with substantially increased urinary excretion of bile alcohol glucuronides. By the age of 11 years, he had developed a profile of cholanoids in plasma and urine that closely resembled the pattern seen in cerebrotendinous xanthomatosis (CTX). Sequencing of the sterol 27-hydroxylase gene ( CYP27A) showed that he was homozygous for a deletion (525/526delG) that causes a frameshift and a premature stop codon. This genotype has previously been described in an adult female with classical symptoms of CTX (tendon xanthomata, cataracts and deteriorating cognitive function). A review of past medical histories of a group of patients with CTX revealed that prolonged neonatal cholestatic jaundice was common. The family histories also revealed fetal and neonatal deaths among siblings of patients with CTX. We conclude that defective activity of cholesterol 27-hydroxylase can lead to neonatal cholestatic jaundice ('hepatitis of infancy'), which may be self-limiting. After a latent period, however, progressive accumulation of cholesterol and cholestanol can lead to the xanthomata, neurodegeneration, cataracts and atherosclerosis that are typical of CTX. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene, with apparent lethality in male embryos. However, recent studies indicate that mutations in the MECP2 gene can cause congenital encephalopathy, an Angelman-like phenotype and even nonspecific mental retardation in males. We report on a 10-year-old boy with moderate mental retardation, hypotonia, obesity and gynaecomastia and a de novo 2-bp deletion in the MECP2 gene that resulted in a frameshift and premature stop codon. As some of the clinical features were suggestive of the Prader–Willi syndrome, it might be worthwhile screening for MECP2 mutations in patients with an atypical Prader–Willi phenotype but without the characteristic abnormalities on chromosome 15q. This report contributes to the phenotypic knowledge of male patients with MECP2 mutations. Moreover, this is the first reported male case of a de novo MECP2 mutation. [ABSTRACT FROM AUTHOR]

Low fetal fraction (LFF) of cell-free DNA in non-invasive prenatal testing (NIPT) is associated with an increased risk of aneuploidy. Case reports and studies reporting on NIPT for sex chromosome aneuploidies or aneuploidies other than Trisomy 21, 18, or 13, or NIPT in multiple pregnancies were excluded. LFF is associated with aneuploidy and likely associated with adverse pregnancy outcome. [Extracted from the article]

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared., (Copyright 2005 Wiley-Liss, Inc.)