Lessons learned from unsolicited findings in clinical exome sequencing of 16,482 individuals.

Unsolicited findings (UFs) are uncovered unintentionally and predispose to a disease unrelated to the clinical question. The frequency and nature of UFs uncovered in clinical practice remain largely unexplored. We here evaluated UFs identified during a 5-year period in which 16,482 index patients received clinical whole-exome sequencing (WES).

The impact of unsolicited findings in clinical exome sequencing, a qualitative interview study.

Unsolicited findings (UFs) in clinical exome sequencing are variants that are unrelated to the initial clinical question the DNA test was performed for, but that may nonetheless be of medical relevance to patients and/or their families. There is limited knowledge about the impact of UFs on patients' lives. In order to characterise patient perceptions of the impact of an UF, we conducted 20 semi-structured face-to-face interviews with patients and/or their relatives to whom an UF predisposing to oncological disease (n = 10) or predisposing to a cardiac condition (n = 10) had been disclosed.

Growth, health, and motor development of 5-year-old children born after preimplantation genetic diagnosis.

Objective: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD).

Design: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC).

Setting: University hospital.

Perinatal follow-up of children born after preimplantation genetic diagnosis between 1995 and 2014.

Purpose: We aim to evaluate the safety of PGD. We focus on the congenital malformation rate and additionally report on adverse perinatal outcome.

Methods: We collated data from a large group of singletons and multiples born after PGD between 1995 and 2014.

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation.

Aims: Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.

Manifest disease, risk factors for sudden cardiac death, and cardiac events in a large nationwide cohort of predictively tested hypertrophic cardiomyopathy mutation carriers: determining the best cardiological screening strategy.

Aims: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for sudden cardiac death (SCD), and cardiac events during follow-up in predictively tested-not known to have a clinical diagnosis of HCM before the DNA test-carriers of a sarcomeric gene mutation and associations with age and gender to determine the best cardiological screening strategy.

Methods And Results: One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease.

Expanding the spectrum of FOXC1 and PITX2 mutations and copy number changes in patients with anterior segment malformations.

Purpose: Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD.

Methods: The patients were examined for FOXC1 and PITX2 copy number changes and mutations using MLPA (multiplex ligation-dependent probe amplification) and direct sequencing.

The unfolding clinical spectrum of holoprosencephaly due to mutations in SHH, ZIC2, SIX3 and TGIF genes.

Holoprosencephaly is a severe malformation of the brain characterized by abnormal formation and separation of the developing central nervous system. The prevalence is 1:250 during early embryogenesis, the live-born prevalence is 1:16 000. The etiology of HPE is extremely heterogeneous and can be teratogenic or genetic.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy diagnostic task force criteria: impact of new task force criteria.

Background: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted.

Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation.

Two mechanisms are generally proposed to explain right precordial ST-segment elevation in Brugada syndrome: 1) right ventricular (RV) subepicardial action potential shortening and/or loss of dome causing transmural dispersion of repolarization; and 2) RV conduction delay. Here we report novel mechanistic insights into ST-segment elevation associated with a Na(+) current (I(Na)) loss-of-function mutation from studies in a Dutch kindred with the COOH-terminal SCN5A variant p.Phe2004Leu.

Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21.

Background: Atrial Fibrillation (AF), the most common cardiac arrhythmia, is a significant public health problem in the United States, affecting approximately 2.2 million Americans. Recently, several chromosomal loci and genes have been found to be associated with familial AF.