Huntington disease (HD) is an adult-onset, autosomal dominant inherited human neurodegenerative disorder characterized by hyperkinetic involuntary movements, including motor restlessness and chorea, slowing of voluntary movements and cognitive impairment. Selective regional neuron loss and gliosis in striatum, cerebral cortex, thalamus, subthalamus and hippocampus are well recognized as neuropathological correlates for the clinical manifestations of HD. The underlying genetic mutation is the expansion of CAG trinucleotide repeats (coding for polyglutamines) to 36-121 copies in exon 1 of the HD gene. The HD mRNA and protein product (huntingtin) show widespread distribution, and thus much remains to be understood about the selective and progressive neurodegeneration in HD. To create an experimental animal model for HD, transgenic mice were generated showing widespread expression of full-length human HD cDNA with either 16, 48 or 89 CAG repeats. Only mice with 48 or 89 CAG repeats manifested progressive behavioural and motor dysfunction with neuron loss and gliosis in striatum, cerebral cortex, thalamus and hippocampus. These animals represent clinically relevant models for HD pathogenesis, and may provide insights into the underlying pathophysiological mechanisms of other triplet repeat disorders.

Individuals containing double variant MTHFR mutations on one allele (cis) cannot be distinguished between compound heterozygotes (trans) for 677CT and 1298AC mutations in routine clinical testing, a genotype associated with thrombophilia. Such patients could be inappropriately counseled for being at high risk for thrombotic episodes. Until information regarding prevalence and the clinical consequences of this double variant (cis) allele becomes available, caution should be used in interpreting the genotyping results of compound heterozygosity for 677CT and 1298AC.

Purpose: We expect that the mutation panel currently recommended for preconception/prenatal CF carrier screening will be modified as new information is learned regarding the phenotype associated with specific mutations and allele frequencies in various populations. One such example is the I148T mutation, originally described as a severe CF mutation. After implementation of CF population-based carrier screening, we learned that I148T exists as a complex allele with 3199del6 in patients with clinical CF, whereas asymptomatic compound heterozygotes for I148T and a second severe CF mutation were negative for 3199del6. Methods: We performed reflex testing for 3199del6 on 663 unrelated specimens, including I148T heterozygotes, compound heterozygotes, and a homozygous individual. Results: Less than 1% of I148T carriers were also positive for 3199del6. Excluding subjects tested because of a suspected or known CF diagnosis or positive family history, 0.6% of I148T-positive individuals were also positive for 3199del6. We identified 1 I148T homozygote and 6 unrelated compound heterozygous individuals with I148T and a second CF variant (2 of whom also carried 3199del6). In addition, one fetus with echogenic bowel and one infertile male were heterozygous for I148T (3199del6 negative). Conclusions:Reflex testing for 3199del6 should be considered whenever I148T is identified. Reflex testing is of particular importance for any symptomatic patient or whenever one member of a couple carries a deleterious CF mutation and the other member is an I148T heterozygote. Further population data are required to determine if I148T, in the absence of 3199del6, is associated with mild or atypical CF or male infertility. Genet Med 2004:6(5):421-425. Key Words: cystic fibrosis, mutation analysis, 3199del6, I148TOver 1000 cystic fibrosis (CF) mutations have been identified; most are rare, having been detected in only one family. 1 In 2001, the ACMG 2 and ACOG 3 developed a panethnic panel of 25 common mutations with a frequency Ն 0.1% in the general population and recommended that all Caucasians who are either pregnant or considering pregnancy be screened. ACMG/ ACOG also recommend that screening be made available to individuals in lower risk ethnic groups. We expect that the mutation panel will be modified as new information arises regarding the phenotype associated with specific mutations and allele frequencies in various populations. The I148T mutation, which is currently included in the panel, was first reported in 1990 as a severe mutation 4 -7 and accounted for 9% of FrenchCanadian CF mutations. 8 After implementation of CF population-based carrier screening, two studies noted a Ͼ 100-fold increase in the frequency of I148T among individuals undergoing carrier screening compared to patients with clinical CF. 9 -10 Further studies revealed a second mutation, 3199del6, in-cis with I148T in affected patients, 9,11 a finding previously reported in 1998. 1 The 3199del6 mutation was not present in asymptomatic compound heterozygous individuals w...

The utility of molecular diagnostics in clinical practice has been steadily increasing and is expected to continue to do so as the applications of genomic medicine increase. The goal of this article was to describe the roles and responsibilities of genetic counselors who work in the customer service area of molecular diagnostics laboratories.In this role, genetic counselors provide recommendations to clinicians on issues that are specific to DNA-based testing. This article will address some issues that are specifically relevant to disease genetic tests. Many molecular diagnostic laboratories employ genetic counselors, who have extensive training in how to communicate genetic information, to provide information in the preanalytic, analytic, and postanalytic stages of testing. To maximize the quality of the service, it is important to establish an understanding of what can be expected of both the practitioner and the laboratory genetic counselor. Although some complications in the laboratory cannot be anticipated, discussing the case with the laboratory genetic counselors beforehand may avert certain problems.This article discusses real cases from laboratory genetic counselors to illustrate issues that arise due to technical difficulties and the inherent limitations of molecular testing. The summary describes practical ways in which clinicians and laboratory personnel can work together to either avoid or, when unavoidable, better manage problems and delays. The responsibilities of genetic counselors working in molecular diagnostics are discussed. Genet Med

The purpose of this work is to define rare variants of cystic fibrosis (CF) that are potential sources of error and can confound molecular genetic testing methods. We performed routine , clinical CF mutation screening using a laboratory-developed test and the oligonucleotide ligation assay reagents from Abbott/Celera. In this report, we describe 11 unique allele drop outs [3849 ؉ 10kb C>T (NM_000492.