Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21–q23.2 in three unrelated, consanguineous Pakistani ...families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic-hearing-impairment phenotype within the three families, and neither mutation was identified in ethnically matched controls or within variant databases. Individuals homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters’ cells, the sulcus epithelium, the basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner-ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI-affected families defines a gene that is associated with ARNSHI.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated ...individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.
Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic ...etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.
Atherosclerotic cardiovascular disease (CVD) is a major health problem in the United States and around the world. Evidence accumulated over decades convincingly demonstrates that family history in a ...parent or a sibling is associated with atherosclerotic CVD, manifested as coronary heart disease, stroke, and/or peripheral arterial disease. Although there are several mendelian disorders that contribute to CVD, most common forms of CVD are believed to be multifactorial and to result from many genes, each with a relatively small effect working alone or in combination with modifier genes and/or environmental factors. The identification and the characterization of these genes and their modifiers would enhance prediction of CVD risk and improve prevention, treatment, and quality of care. This scientific statement describes the approaches researchers are using to advance understanding of the genetic basis of CVD and details the current state of knowledge regarding the genetics of myocardial infarction, atherosclerotic CVD, hypercholesterolemia, and hypertension. Current areas of interest and investigation--including gene-environment interaction, pharmacogenetics, and genetic counseling--are also discussed. The statement concludes with a list of specific recommendations intended to help incorporate usable knowledge into current clinical and public health practice, foster and guide future research, and prepare both researchers and practitioners for the changes likely to occur as molecular genetics moves from the laboratory to clinic.
In addition to rare genetic variants and the
locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the
locus for IPF ...and interstitial lung abnormalities (ILAs) is unknown.
We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the
region on IPF, ILA, and ILA progression.
We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the
region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression.
We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio OR per SD of the score, 3.1;
= 7.1 × 10
) and PRS-NO-M5B (OR per SD, 2.8;
= 2.5 × 10
) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants.
A common genetic variant risk score complements the
variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.
Carney complex is a familial multiple neoplasia disorder with characteristic features such as cardiac and cutaneous myxomas and spotty pigmentation of the skin. Clinical genetic analyses have shown ...that Carney complex is transmitted in an autosomal dominant way and can present with a wide array of other tumours, such as psammomatous melanotic schwannoma, testicular Sertoli-cell tumours, and pituitary adenomas. Molecular genetic studies show that mutations in the
PRKAR1A gene, encoding the R1α regulatory subunit of cyclic-AMP-dependent protein kinase A, are the cause of Carney complex in most patients. Investigation of genetically engineered animal models confirms the role of
PRKAR1A as a tumour suppressor and has begun to elaborate mechanisms underlying tumorigenesis in this disorder. Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the
MYH8 gene that encodes perinatal myosin.
Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C→T) is a ...known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate–dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 “Q” allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 95% confidence interval 1.16–1.99,
P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.
Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously ...identified PRKAR1A (regulatory subunit 1α of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a+/- mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a+/- mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a+/- mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.
Cardiovascular abnormalities, especially structural congenital heart defects, commonly occur in malformation syndromes and genetic disorders. Individuals with syndromes comprise a significant ...proportion of those affected with selected congenital heart defects such as complete atrioventricular canal, interrupted arch type B, supravalvar aortic stenosis, and pulmonary stenosis. As these individuals age, they contribute to the growing population of adults with special health care needs. Although most will require longterm cardiology follow-up, primary care providers, geneticists, and other specialists should be aware of (1) the type and frequency of cardiovascular abnormalities, (2) the range of clinical outcomes, and (3) guidelines for prospective management and treatment of potential complications. This article reviews fundamental genetic, cardiac, medical, and reproductive issues associated with common genetic syndromes that are frequently associated with a cardiovascular abnormality. New data are also provided about the cardiac status of adults with a 22q11.2 deletion and with Down syndrome.
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