K Martens

Autosomal-dominant microtia linked to five tandem copies of a copy-number-variable region at chromosome 4p16.

Recently, large-scale benign copy-number variations (CNVs)--encompassing over 12% of the genome and containing genes considered to be dosage tolerant for human development--were uncovered in the human population. Here we present a family with a novel autosomal-dominantly inherited syndrome characterized by microtia, eye coloboma, and imperforation of the nasolacrimal duct. This phenotype is linked to a cytogenetically visible alteration at 4pter consisting of five copies of a copy-number-variable region, encompassing a low-copy repeat (LCR)-rich sequence. We demonstrate that the approximately 750 kb amplicon occurs in exact tandem copies. This is the first example of an amplified CNV associated with a Mendelian disorder, a discovery that implies that genome screens for genetic disorders should include the analysis of so-called benign CNVs and LCRs.

Deletion of C2orf34, PREPL and SLC3A1 causes atypical Hypotonia-Cystinuria Syndrome

Background: Hypotonia–cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. The deletions differ in size and the number of genes involved. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Objective: Clinical and molecular analysis of two siblings who presented with an atypical HCS phenotype. Methods: Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. Results: HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency documented in patient 2. Conclusions: We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome. These patients facilitate the elucidation of the contribution of each gene to the phenotype in the different 2p21 deletion syndromes.

Global distribution of the most prevalent deletions causing hypotonia-cystinuria syndrome

Hypotonia–cystinuria syndrome (HCS) is a recessive disorder caused by microdeletions of SLC3A1 and PREPL on chromosome 2p21. Patients present with generalized hypotonia at birth, failure to thrive, growth retardation and cystinuria type I. While the initially described HCS families live in small regions in Belgium and France, we have now identified HCS alleles in patients and carriers from the Netherlands, Italy, Canada and United States of America. Surprisingly, among the nine deletions detected in those patients, only one novel deletion was found. Furthermore, one previously described deletion was found six times, another twice. Finally, we have investigated the frequency of both deletions using a random Belgian cohort. Given the global occurrence, HCS should be considered in the differential diagnosis of neonatal hypotonia.

The CAREGENE study: ACE gene I/D polymorphism and effect of physical training on aerobic power in coronary artery disease

In coronary artery disease (CAD) the individual variation in aerobic power and the response to physical training are largely unexplained.1 The gene coding for the angiotensin converting enzyme (ACE) is expressed in several types of somatic cells, including vascular cells, heart, lung, and muscles.2 Intron 16 contains a polymorphism characterised by the presence (insertion (I)) or absence (deletion (D)) of a 287 bp Alu repeat sequence,3 which has been associated with endurance related phenotypes and the response to training.4 The objective of the present study was to investigate the role of ACE I/D polymorphism on aerobic power and its response to physical training in patients with CAD enrolled in the CAREGENE (cardiac rehabilitation and genetics of exercise performance) study. Biologically unrelated white patients with CAD (mean (SE) age 56 (0.3) years) who had achieved evident exhaustion during graded cycle ergometer testing before and after three months of physical training (three sessions weekly) from 1990 through 2001 (n  =  1095) were eligible for inclusion. The methods for graded exercise testing and training have been …

The caregene study: muscle-specific creatine kinase gene and aerobic power in coronary artery disease

In 927 biologically unrelated Caucasian patients with coronary artery disease it was investigated whether the NcoI restriction fragment length polymorphism of the muscle-specific creatine kinase (CKMM) gene is associated with aerobic power and with the response to physical training. Physical training significantly (P<0.001) increased peak oxygen consumption in the GG, AG and AA NcoI genotypes. Covariate-adjusted peak oxygen consumption at baseline, after training and the response to training were not different across CKMM NcoI genotypes.

Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome

Hypotonia–cystinuria syndrome (HCS) and 2p21 deletion syndrome are two recessive contiguous gene deletion syndromes associated with cystinuria type I. In HCS patients, only SLC3A1 and PREPL are disrupted. In the 2p21 deletion syndrome, two additional genes (C2orf34 and PPM1B) are lost. Molecular analysis of the SLC3A1/PREPL locus was performed in the patients using quantitative polymerase chain reaction (PCR) methods. HCS in both siblings was confirmed with the deletion screen of the SLC3A1/PREPL locus. Fine mapping of the breakpoint revealed a deletion of 77.4 kb, including three genes: SLC3A1, PREPL and C2orf34. Features not present in classical HCS were a mild/moderate mental retardation and a respiratory chain complex IV deficiency. We report the first patients with a deletion of SLC3A1, PREPL and C2orf34. They present with a phenotype intermediate between HCS and 2p21 deletion syndrome.