Search

Objective To examine the genetic mutations in the first UK cohort of patients with cystinuria with preliminary genotype/phenotype correlation. Patients and Methods DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) were used to identify the mutations in 74 patients in a specialist cystinuria clinic in the UK. Patients with type A cystinuria were classified into two groups: Group M patients had at least one missense mutation and Group N patients had two alleles of all other types of mutations including frameshift, splice site, nonsense, deletions and duplications. The levels of urinary dibasic amino acids, age at presentation of disease, number of stone episodes and interventions were compared between patients in the two groups using the Mann–Whitney U-test. Results In all, 41 patients had type A cystinuria, including one patient with a variant of unknown significance and 23 patients had type B cystinuria, including six patients with variants of unknown significance. One patient had three sequence variants in SLC7A9; however, two are of unknown significance. Three patients had type AB cystinuria. Three had a single mutation in SLC7A9. No identified mutations were found in three patients in either gene. There were a total of 88 mutations in SLC3A1 and 55 mutations in SLC7A9. There were 23 pathogenic mutations identified in our UK cohort of patients not previously published. In patients with type A cystinuria, the presence of a missense mutation correlated to lower levels of urinary lysine (mean [se] 611.9 [22.65] vs 752.3 [46.39] millimoles per mole of creatinine [mm/MC]; P=0.02), arginine (194.8 [24.83] vs 397.7 [15.32] mm/MC; P

15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n = 83) were compared with frequencies in the non-deleted cohort (n = 14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR = 6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.

At present, women at increased risk of fetal Down syndrome because of advanced maternal age, an abnormal screening test result, or a previous affected child are offered genetic amniocentesis with full fetal karyotype analysis. The advent of reliable and efficient rapid molecular techniques for identifying numeric chromosome abnormalities raises the question of whether a full fetal karyotype analysis is necessary when samples are analyzed solely because the risk of Down syndrome is increased. Without complete karyotyping, there is a risk that chromosomal abnormalities not demonstrated by rapid trisomy testing will go undiagnosed. However, some of these fetuses would have a malformation evident on ultrasound scanning, and a complete karyotype analysis would be offered. At the same time, some abnormal genotypes will have no significant phenotypic sequelae visible by ultrasound, some may be inherited and not associated with phenotypic abnormalities, and others will be of uncertain significance, raising parental anxiety and possibly resulting in unnecessary pregnancy terminations. This retrospective review included 32,674 pregnant women living in or near London who had invasive prenatal diagnosis from 1996 to 2002. More than three fourths of samples (24,891) were from women referred chiefly for Down syndrome testing. Among these samples were 118 sex chromosome abnormalities and 153 autosomal abnormalities not found by rapid testing (0.62%). Fifty-five of the 118 pregnancies with fetal sex chromosome abnormalities delivered at term; in 44 the outcome was unknown and 19 miscarried or were terminated. Among the 153 pregnancies with fetal autosomal abnormalities, the prognosis was classified as good for 98, uncertain for 37, and poor for 18. The 98 cases with a good prognosis included 46 live-born infants, 3 pregnancy terminations, one case each of intrauterine death and miscarriage, and 47 whose outcome was unknown. Of 37 cases with an uncertain prognosis, 20 resulted in a live-born infant, 5 were terminations, and in 12, the outcome was not ascertained. Among 18 cases with a poor prognosis were a single live-born infant, 2 miscarriages, 11 terminations, and 4 with unknown outcomes. In a separate analysis of phenotypically abnormal children under age 5 brought in for evaluation from 1995 to 1997, there were 90 nonnumeric chromosome abnormalities of which 78 were unbalanced and 12 were balanced chromosome rearrangements. Considering that there were approximately 46,430 live births per year in the referral region over the study period, the investigators estimated that the proportion of living children with unbalanced chromosome abnormalities causing concern in the first 5 years of life was 0.06%. The risk of having an infant with a nonnumeric unbalanced chromosomal abnormality was no higher in women at increased risk of a Down syndrome pregnancy than in those lacking such risk. The investigators concluded that if prenatal karyotyping was replaced by molecular trisomy testing for women at risk of a Down syndrome birth, substantial financial savings would result, and the results would be available rapidly and would not be ambiguous. In addition, anxiety will be lessened, and possibly unneeded terminations of pregnancy would be avoided.

DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria-SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β-sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X-inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X-inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non-syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003

Summary background Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterized by uniglandular or multiglandular parathyroid tumours that occur in the absence of other endocrine tumours. The disorder may represent either an early stage of multiple endocrine neoplasia type 1 (MEN1), or an allelic variant of MEN1, or a distinct entity involving another locus. We have explored these possibilities in seven families in whom primary hyperparathyroidism occurred as the sole endocrinopathy. methods Seven FIHP families were ascertained and venous blood samples obtained from 35 members (17 affected and 18 unaffected) for DNA sequence analysis of the MEN1 gene. The mean (± SD) follow-up period in the 17 affected members was 15·06 (± 8·83) years. results Four heterozygous germline mutations of the MEN1 gene were identified. These consisted of two 4-bp intragenic deletions that would result in prematurely truncated proteins, and two missense (Asp153Val and Ala411Pro) mutations. Furthermore, analysis of parathyroid tumour DNA from one individual revealed a loss of the wild-type allele and retention of the mutant allele, consistent with Knudson's ‘two-hit’ model of hereditary cancer and a tumour suppressor role for MEN1 in FIHP. conclusions Our results provide further support for FIHP being a distinct allelic variant of MEN1, and an analysis of the 16 mutations reported to date indicate that FIHP is associated with a higher frequency of missense MEN1 mutations.

Asthma is a complex syndrome in which bronchial inflammation and smooth muscle hyperactivity lead to labile airflow obstruction. The commonest form of asthma is that due to atopy, which is an immune disorder where production of IgE to inhaled antigens leads to bronchial mucosal inflammation. The ultimate origins of asthma are interactive environmental and genetic factors. The genetics is acknowledged to be heterogeneous, and one chromosomal region of interest and controversy has been 11q13. To clarify the nature of the chromosome 11q13 effect in atopy and asthma, we conducted a genetic association study in subjects with marked atopic asthma and matched controls, which incorporated the study of 13 genetic variants over a distance of 10-12 cM and which took account of detailed immune and clinical phenotyping. Association with high IgE levels was limited to the interval flanked by D11S1335 and CD20 in a 0.8-Mb interval and was greatest for variants of Fc epsilon RI beta and HTm4; these variants also associated with asthma (recurrent wheeze with labile airflow obstruction and need for regular inhaler treatment). At the more telomeric marker, D11S480, variants associated with asthma, but not with high IgE levels. The data might support the possibility of multiple loci relevant to atopic asthma on chromosome 11q13.

We describe two sibs with pulmonary hypoplasia and anophthalmia ; one also had a number of other malformations. Only one other broadly similar case could be found in the literature, and it was an isolated occurrence. The condition is named the Matthew-Wood syndrome.