19 research outputs found
Clinical implications and considerations for evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines
Abstract Clinical genetics laboratories have recently adopted guidelines for the interpretation of sequence variants set by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP). The use of in silico algorithms to predict whether amino acid substitutions result in human disease is inconsistent across clinical laboratories. The clinical genetics community must carefully consider how in silico predictions can be incorporated into variant interpretation in clinical practice. Please see related Research article: https://doi.org/10.1186/s13059-017-1353-
The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine
Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic α cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and ARG1 sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the Gcgr−/− knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in GCGR. Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease. Keywords: Glucagon receptor, Newborn screening, GCGR mutation, Hyperaminoacidemia, Mahvash disease, Pancreatic α cell hyperplasia (ACH), Pancreatic neuroendocrine tumor (PNET
Analysis of Copy Number Variants on Chromosome 21 in Down Syndrome-Associated Congenital Heart Defects
One in five people with Down syndrome (DS) are born with an atrioventricular septal defect (AVSD), an incidence 2000 times higher than in the euploid population. The genetic loci that contribute to this risk are poorly understood. In this study, we tested two hypotheses: (1) individuals with DS carrying chromosome 21 copy number variants (CNVs) that interrupt exons may be protected from AVSD, because these CNVs return AVSD susceptibility loci back to disomy, and (2) individuals with DS carrying chromosome 21 genes spanned by microduplications are at greater risk for AVSD because these microduplications boost the dosage of AVSD susceptibility loci beyond a tolerable threshold. We tested 198 case individuals with DS+AVSD, and 211 control individuals with DS and a normal heart, using a custom microarray with dense probes tiled on chromosome 21 for array CGH (aCGH). We found that neither an individual chromosome 21 CNV nor any individual gene intersected by a CNV was associated with AVSD in DS. Burden analyses revealed that African American controls had more bases covered by rare deletions than did African American cases. Inversely, we found that Caucasian cases had more genes intersected by rare duplications than did Caucasian controls. We also showed that previously DS+AVSD (DS and a complete AVSD)-associated common CNVs on chromosome 21 failed to replicate. This research adds to the swell of evidence indicating that DS-associated AVSD is similarly heterogeneous, as is AVSD in the euploid population
The distribution of single recombination events across the long arm of 21q by population.
<p>21q was divided into 66 500</p
Comparison of the relationship between hotspot usage between MI and MII cases and Controls.
<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099560#pone-0099560-g004" target="_blank">Figure 4A and 4B</a> represent MI and MII cases respectively with only one recombinant event on 21q. The solid line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along normally segregating chromosomes 21. The dotted line represents the relationship between the number of hotspots per bin and the proportion of recombination per bin along chromosomes 21 from MI errors (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099560#pone-0099560-g004" target="_blank">figure 4A</a>) and MII errors (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0099560#pone-0099560-g004" target="_blank">figure 4B</a>).</p
Beta coefficient/slope values for hotspots variable adjusted by bin variable and stratified by meiotic outcome group and number of recombinants on chr21.
<p>Beta coefficients/slopes that are significantly different from zero are marked with an asterisk*.</p
The distribution of the distal recombinant of a double recombinant event across the long arm of 21q by population.
<p>21q was divided into 66 500</p
The distribution of the proximal recombinant of a double recombinant event across the long arm of 21q by population.
<p>21q was divided into 66 500</p