Whole-exome sequencing for diagnosis of hereditary ichthyosis.

BACKGROUND: Hereditary ichthyosis constitutes a diverse group of cornification disorders. Identification of the molecular cause facilitates optimal patient care. OBJECTIVE: We wanted to estimate the diagnostic yield of applying whole-exome sequencing (WES) in the routine genetic workup of inherited ichthyosis. METHODS: During a 3-year-period, all ichthyosis patients, except X-linked and mild vulgar ichthyosis, consecutively admitted to a university hospital clinic were offered WES with subsequent analysis of ichthyosis-related genes as a first-line genetic investigation. Clinical and molecular data have been collected retrospectively. RESULTS: Genetic variants causative for the ichthyosis were identified in 27 of 34 investigated patients (79.4%). In all, 31 causative mutations across 13 genes were disclosed, including 12 novel variants. TGM1 was the most frequently mutated gene, accounting for 43.7% of patients suffering from autosomal recessive congenital ichthyosis (ARCI). CONCLUSION: Whole-exome sequencing appears an effective tool in disclosing the molecular cause of patients with hereditary ichthyosis seen in clinical practice and should be considered a first-tier genetic test in these patients.

[Diagnostic DNA testing for Huntington disease]. / Diagnostisk DNA-testing for Huntingtons sykdom.

Direct DNA testing for the autosomal dominant neurodegenerative disorder, Huntington's disease, may be performed in a diagnostic setting, as a presymptomatic procedure or prenatally. This paper is intended for physicians practising outside departments of medical genetics who are considering diagnostic testing of patients presenting with symptoms or signs compatible with Huntington's disease. It offers a brief overview of practically relevant clinical, epidemiological, molecular and legal aspects of diagnostic genetic testing for Huntington's disease in Norway. We stress the need for adequate information before sampling and after the test has been performed, and for close contact with the genetics centre which offers the test for Huntington's disease and provides genetic counselling. As with other diagnostic tests, the treating physician is responsible for informing the patient about the result of the test and for ensuring adequate follow-up. The physician will often need the assistance of an expert in clinical genetics. A positive DNA test for Huntington's disease in a patient may have a profound impact on family members, who should be offered genetic counselling and support. Since asymptomatic at-risk family members may ask for a presymptomatic test in the future, diagnostic confirmation at the DNA level is warranted in any person examined because of clinical signs of Huntington's disease, even when the clinical diagnosis is considered unquestionable.

[Genetic counseling in presymptomatic testing for Huntington disease]. / Genetisk veiledning ved presymptomatisk testing for Huntingtons sykdom.

Norwegian law and international guidelines require genetic counselling before, during and after presymptomatic testing for Huntington's disease. The genetic counselling of at-risk persons who considers taking tests, includes explanation of the possible implications of a test result for both participant and relatives. The test is performed only when explicitly requested by the participant and after informed consent. The participant decides if and when the test should be conducted. The participant also has major influence on the timing of the consecutive phases of the testing procedure, in compliance with medical and ethical recommendations. This paper reviews main issues raised during genetic counselling and the preparation period preceding the test and communication of the test result. We illustrate different individual situations and backgrounds for considering presymptomatic testing for Huntington's disease by describing three anonymized cases and associated pedigrees.