Objective:Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic ...factors (i.e., “second hits”) that may contribute to schizophrenia expression.Method:Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.Results:Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.Conclusions:The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.
Whereas noninvasive prenatal screening for aneuploidies is widely implemented, there is an increasing need for universal approaches for noninvasive prenatal screening for monogenic diseases. Here, we ...present a cost-effective, generic cell-free fetal DNA (cffDNA) haplotyping approach to scan the fetal genome for the presence of inherited monogenic diseases.
Families participating in the preimplantation genetic testing for monogenic disorders (PGT-M) program were recruited for this study. Two hundred fifty thousand single-nucleotide polymorphisms (SNPs) captured from maternal plasma DNA along with genomic DNA from family members were massively parallel sequenced. Parental genotypes were phased via an available genotype from a close relative, and the fetal genome-wide haplotype and copy number were determined using cffDNA haplotyping analysis based on estimation and segmentation of fetal allele presence in the maternal plasma.
In all families tested, mutational profiles from cffDNA haplotyping are consistent with embryo biopsy profiles. Genome-wide fetal haplotypes are on average 97% concordant with the newborn haplotypes and embryo haplotypes.
We demonstrate that genome-wide targeted capture and sequencing of polymorphic SNPs from maternal plasma cell-free DNA (cfDNA) allows haplotyping and copy-number profiling of the fetal genome during pregnancy. The method enables the accurate reconstruction of the fetal haplotypes and can be easily implemented in clinical practice.
Schinzel-Giedion syndrome is characterized by severe mental retardation, distinctive facial features and multiple congenital malformations; most affected individuals die before the age of ten. We ...sequenced the exomes of four affected individuals (cases) and found heterozygous de novo variants in SETBP1 in all four. We also identified SETBP1 mutations in eight additional cases using Sanger sequencing. All mutations clustered to a highly conserved 11-bp exonic region, suggesting a dominant-negative or gain-of-function effect.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each ...of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Congenital diaphragmatic hernia (CDH) is characterized by a defective closure of the diaphragm occurring as an isolated defect in 60% of cases. Lung size, liver herniation, and pulmonary ...circulation are major prognostic indices. Isolated CDH genetics is heterogeneous and poorly understood. Whether genetic lesions are also outcome determinants has never been explored.
Objectives
To identify isolated CDH genetic causes, to fine map the mutational burden, and to search for a correlation between the genotype and the disease severity and outcome.
Methods
Targeted massively parallel sequencing of 143 human and mouse CDH causative and candidate genes in a cohort of 120 fetuses with isolated CDH and detailed outcome measures.
Results
Pathogenic and likely pathogenic variants were identified in 10% of the cohort. These variants affect both known CDH causative genes, namely, ZFPM2, GATA4, and NR2F2, and new genes, namely, TBX1, TBX5, GATA5, and PBX1. In addition, mutation burden analysis identified LBR, CTBP2, NSD1, MMP14, MYOD1, and EYA1 as candidate genes with enrichment in rare but predicted deleterious variants. No obvious correlation between the genotype and the phenotype or short‐term outcome has been found.
Conclusion
Targeted resequencing identifies a genetic cause in 10% of isolated CDH and identifies new candidate genes.
What's already known about this topic?
Congenital diaphragmatic hernia (CDH) is thought to have an important genetic component. Nevertheless, CDH genetics remains poorly understood, especially for isolated form. The correlation of isolated CDH severity and outcome with the genotype has not been investigated.
What does this study add?
Targeted massive parallel sequencing identifies isolated CDH likely causative variants in 10% of cases and identifies new candidate genes.
Genomic imprinting, the differential expression of paternal and maternal alleles, is involved in the regulation of embryonic and fetal growth and development. In this review, we focus on the genetics ...of a disorder caused by a global defect in genomic imprinting, the hydatidiform mole. The ratio between the maternal and paternal genomes is critical in determining the development of both the embryonic and extraembryonic tissues, with an excess of paternally derived chromosomes leading to a complete (no maternal genome) or partial (lower amount of maternal chromosomes) mole. The recent identification and molecular studies in biparental complete moles may yield more insight into the regulation of imprinting during gametogenesis.
A
de novo
0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of ...in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders:
DMTN
,
EGR3
,
FGF17
,
LGI3
,
PHYHIP
, and
PPP3CC
.
Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. ...By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Ehlers-Danlos syndrome (EDS), dermatosparaxis type, is a recessively inherited connective tissue disorder caused by deficient activity of ADAMTS-2, an enzyme that cleaves the aminoterminal ...propeptide domain of types I, II, and III procollagen. Only 10 EDS dermatosparaxis patients have been reported, all presenting a recognizable phenotype with characteristic facial gestalt, extreme skin fragility and laxity, excessive bruising, and sometimes major complications due to visceral and vascular fragility.
We report on five new EDS dermatosparaxis patients and provide a comprehensive overview of the current knowledge of the natural history of this condition.
We identified three novel homozygous loss-of-function mutations (c.2927_2928delCT, p.(Pro976Argfs*42); c.669_670dupG, p.(Pro224Argfs*24); and c.2751-2A>T) and one compound heterozygous mutation (c.2T>C, p.? and c.884_887delTGAA, p.(Met295Thrfs26*)) in ADAMTS2 in five patients from four unrelated families. Three of these displayed a phenotype that was strikingly milder than that of previously reported patients.
This study expands the clinical and molecular spectrum of the dermatosparaxis type of EDS to include a milder phenotypic variant and stresses the importance of good clinical criteria. To address this, we propose an updated set of criteria that accurately captures the multisystemic nature of the dermatosparaxis type of EDS.Genet Med 18 9, 882-891.
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