Prenatal cases with rare RIT1 variants causing severe fetal hydrops and death.
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ABSTRACT:
SUBMITTER: Miceikaite I
PROVIDER: S-EPMC8294143 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPathogenic mutations in EVC or EVC2 gene can lead to Ellis-van Creveld (EvC) syndrome, which is a rare autosomal recessive skeletal dysplasia disorder. This study aimed to determine pathogenic gene variations associated with EvC syndrome in fetuses showing ultrasound anomalies.MethodsA 32-year-old pregnant woman from Quanzhou, China was investigated. In her pregnancy examination, the fetus exhibited multiple fetal malformations, including a narrow thorax, short limbs, postaxial polydactyly, cardiac malformations, and separation of double renal pelvis. Karyotype, chromosomal microarray analysis and whole exome sequencing were performed for prenatal genetic etiology analysis.ResultsChromosome abnormalities and copy number variants were not observed in the fetus using karyotype and chromosomal microarray analysis. Using whole exome sequencing, two compound heterozygous variants NM_147127.5:c.[2484G>A(p.Trp828Ter)];[871-2_894del] in EVC2 gene were identified in the fetus as pathogenic variants inherited from parents.ConclusionsThe study is the first to identify two rare compound variants in EVC2 gene in a Chinese family using whole exome sequencing. The application of whole-exome sequencing would be helpful in fetal etiological diagnosis with ultrasound anomalies.
| S-EPMC10568384 | biostudies-literature
Project description:Fetal heart failure and hydrops fetalis may occur due to systemic arteriovenous fistula because of increased cardiac output. Arteriovenous fistula of the central nervous system, liver, bone or vascular tumors such as sacrococcygeal teratoma were previously reported to be causes of intrauterine heart failure. However, coronary arteriovenous fistula was not reported as a cause of fetal heart failure previously. It is a rare pathology comprising 0.2-0.4% of all congenital heart diseases even during postnatal life. Some may remain asymptomatic for many years and diagnosed by auscultation of a continuous murmur during a routine examination, while a larger fistulous coronary artery opening to a low pressure cardiac chamber may cause ischemia of the affected myocardial region due to steal phenomenon and may present with cardiomyopathy or congestive heart failure during childhood. We herein report a neonate with coronary arteriovenous fistula between the left main coronary artery and the right ventricular apex, who presented with hydrops fetalis during the third trimester of pregnancy.
| S-EPMC4160637 | biostudies-other
Project description:Case Report ?A 32-year-old female with a history of three prior pregnancy losses presented for genetic testing following an ultrasonography diagnosis of fetal hydranencephaly. Baby was born via C-section and was noted to have a head circumference of 48?cm, in addition to ocular and cardiac anomalies and dysmorphic features. Whole genome sequencing revealed a homozygous variant in LAMB1 gene. Discussion ?The pathobiogenesis of hydranencephaly is incompletely understood and is attributed to vascular, infectious, or genetic etiology. Herein we present LAMB1 as a monogenic cause of fetal hydranencephaly which was incompatible with life. Previously, LAMB1 -associated phenotype consisted of cobblestone lissencephaly and hydrocephalus, developmental delay, and seizures. Our proband expands the phenotypic spectrum of this malformative encephalopathy.
| S-EPMC7850915 | biostudies-literature
Project description:BackgroundSpondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare inherited chondrodysplasia characterized by abnormal epiphyses, short stature, and flattened vertebral bodies. We investigate the phenotypes and the disease-associated variants of SEDC in two unrelated Chinese families.MethodsWe identified disease-associated variants in two nonconsanguineous families with SEDC using targeted next-generation sequencing and confirmed the variants using Sanger sequencing. We investigated the phenotypes of the patients, including clinical manifestations, bone turnover biomarkers, bone mineral density and skeletal radiographic features.ResultsTwo probands were diagnosed as SEDC according to the phenotypes of disproportionately short-trunk stature, kyphosis, lumbar lordosis and adduction deformity of hips. Radiographs revealed kyphosis and lumbar lordosis, flattened vertebral bodies, compressed femoral heads and shortening of the femurs. Bone mineral density of the probands was lower than that of age- and gender-matched normal children, but bone turnover biomarker levels were within normal range. Two novel heterozygous missense variants (NM_001844.5: c.1654 G>A, NP_001835.3: p.Gly552Arg; NM_001844.5: c.3518G>T, NP_001835.3: p.Gly1173Val) in collagen type II alpha 1 chain (COL2A1) were detected in the two families, which would impair the formation of stable triple-helical type II collagen.ConclusionsWe identified two novel disease-associated variants in COL2A1, which led to severe SEDC. Our findings expanded the gene variant spectrum and phenotypic spectrum of extremely rare type II collagenopathies.
| S-EPMC7057085 | biostudies-literature
Project description:PurposeLeber congenital amaurosis (LCA) is one of the most severe inherited retinal dystrophies with the earliest age of onset. Mutations in the Crumbs homologue 1 (CRB1; OMIM 600105) gene explain 10%-24% of cases with LCA depending on the population. The aim of the present work was to study a fetal mutation associated to LCA in maternal plasma by a new methodology in the noninvasive prenatal diagnosis field: the denaturing High Performance Liquid Chromatography (dHPLC).MethodsThis study presents the case of a compound heterozygous fetus for two mutations in CRB1 (1q3.1-q32.2). dHPLC and automated DNA sequencing were used to detect the paternally inherited fetal mutation in a maternal plasma sample collected at the 12th week of gestation. To test the detection limit of dHPLC, we made serial dilutions of paternal DNA in control DNA.ResultsWe were able to detect the presence of the paternally inherited fetal CRB1 mutation in maternal plasma by dHPLC. Moreover, by comparing chromatograms of serial dilutions to the plasma sample, we could ascertain that the percentage of fetal DNA in maternal plasma was at least 2%. However, the detection of the fetal mutation was not possible by automated DNA sequencing.ConclusionsdHPLC seems to be sensitive enough to detect small amounts of fetal DNA in maternal plasma samples. It could be a useful tool for the noninvasive prenatal detection of paternally inherited point mutations associated with retinopathies.
| S-EPMC2493031 | biostudies-literature
Project description:BackgroundAlthough exome sequencing has a greater overall diagnostic yield than targeted gene panels in the evaluation of nonimmune hydrops fetalis and fetal effusions, the cost-effectiveness of this approach is not known.ObjectiveThis study aimed to evaluate the costs and outcomes of targeted gene panels vs exome sequencing for prenatally diagnosed nonimmune hydrops fetalis and fetal effusions when next-generation sequencing is pursued following nondiagnostic standard nonimmune hydrops fetalis evaluations, including karyotype or chromosomal microarray.Study designA decision-analytical model was designed using TreeAge Pro to compare 10 genetic testing strategies, including a single test only (RASopathy, metabolic, or nonimmune hydrops fetalis-targeted gene panel or exome sequencing), sequential testing (RASopathy panel followed by nonimmune hydrops fetalis panel, metabolic panel followed by nonimmune hydrops fetalis panel, RASopathy panel followed by exome sequencing, metabolic panel followed by exome sequencing, and nonimmune hydrops fetalis panel followed by exome sequencing), and no additional genetic testing. Our theoretical cohort included cases with normal karyotype and/or microarray and excluded cases of alloimmunization and congenital viral infections. As nonimmune hydrops fetalis and fetal effusions can present throughout gestation, whereas pregnancy management options vary depending on gestational age, outcomes were calculated for 3 time intervals: 10 to 18, 18 to 22, and >22 weeks of gestation. The primary outcome was incremental cost per quality-adjusted life year. Additional outcomes included termination of pregnancy, stillbirth, neonatal death, and neonates born with mild, moderate, and severe or profound disease phenotypes. The cost-effectiveness threshold was $100,000 per quality-adjusted life year.ResultsAmong women <18 weeks of gestation, exome sequencing alone was the dominant strategy associated with the lowest costs ($221 million) and the highest quality-adjusted life years (10,288). Strategies with exome sequencing alone or as a sequential test resulted in more terminations but fewer stillbirths, neonatal deaths (NNDs), and affected infants than strategies without exome sequencing. Among women between 18 and 22 weeks of gestation, exome sequencing alone was also associated with the lowest costs ($188 million) and the highest quality-adjusted life years (8734), and similar trends were observed in pregnancy outcomes. Among patients >22 weeks of gestations, when termination was not available, exome sequencing was associated with lower costs ($300 million) and the highest quality-adjusted life years (8492). Exome sequencing was cost-effective up to a cost per test of $50,451 at <18 weeks of gestation, $50,423 at 18 to 22 weeks of gestation, and $9530 at >22 weeks of gestation. Targeted genetic panels and exome sequencing were cost-effective strategies compared with no additional genetic testing.ConclusionFor cases of nonimmune hydrops fetalis and fetal effusions with nondiagnostic karyotype or microarray, next-generation sequencing was cost-effective compared with a strategy without additional genetic testing. For those that undergo next-generation sequencing, exome sequencing was the cost-effective strategy compared with all other testing strategies using targeted gene panels, leading to lower costs and fewer adverse perinatal outcomes. Exome sequencing was cost-effective in a setting without the option for pregnancy termination. These data supported the routine use of exome sequencing when next-generation sequencing is pursued for establishing a genetic diagnosis underlying otherwise unexplained nonimmune hydrops fetalis and fetal effusions.
| S-EPMC9938838 | biostudies-literature
Project description:BackgroundThe cause of most fetal anomalies is not determined prenatally. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Nonimmune hydrops fetalis (NIHF), a fetal abnormality that is often lethal, has numerous genetic causes; the extent to which exome sequencing can aid in its diagnosis is unclear.MethodsWe evaluated a series of 127 consecutive unexplained cases of NIHF that were defined by the presence of fetal ascites, pleural or pericardial effusions, skin edema, cystic hygroma, increased nuchal translucency, or a combination of these conditions. The primary outcome was the diagnostic yield of exome sequencing for detecting genetic variants that were classified as either pathogenic or likely pathogenic according to the criteria of the American College of Medical Genetics and Genomics. Secondary outcomes were the percentage of cases associated with specific genetic disorders and the proportion of variants that were inherited.ResultsIn 37 of the 127 cases (29%), we identified diagnostic genetic variants, including those for disorders affecting the RAS-MAPK cell-signaling pathway (known as RASopathies) (30% of the genetic diagnoses); inborn errors of metabolism and musculoskeletal disorders (11% each); lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders (8% each); and others. Prognoses ranged from a relatively mild outcome to death during the perinatal period. Overall, 68% of the cases (25 of 37) with diagnostic variants were autosomal dominant (of which 12% were inherited and 88% were de novo), 27% (10 of 37) were autosomal recessive (of which 95% were inherited and 5% were de novo), 1 was inherited X-linked recessive, and 1 was of uncertain inheritance. We identified potentially diagnostic variants in an additional 12 cases.ConclusionsIn this large case series of 127 fetuses with unexplained NIHF, we identified a diagnostic genetic variant in approximately one third of the cases. (Funded by the UCSF Center for Maternal-Fetal Precision Medicine and others; ClinicalTrials.gov number, NCT03412760.).
| S-EPMC7650529 | biostudies-literature
Project description:Pathologic amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic amyloid deposits is unclear. Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to amyloid formation. Here, we identified 8 amyloidosis cases with amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal ischemia and death. No other organ contained amyloid. SAA3 mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine peptides identified SAA3 as the predominant protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although amyloid A (AA) amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal peptides indicated that the uterine amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3 amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of amyloidosis and of AA amyloid deposited exclusively in the uterus.
| S-EPMC6137862 | biostudies-literature
Project description:Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.
| S-EPMC8713775 | biostudies-literature
Project description:BackgroundThis study aims to provide genetic diagnoses for 30 cases of fetal skeletal dysplasia, and a molecular basis for the future prenatal diagnosis of fetal skeletal dysplasia.MethodsA total of 30 cases of fetal skeletal dysplasia detected with ultrasound between January 2014 and June 2017 were analyzed. Among these fetuses, 15 fetuses had local skeletal malformations, while 15 fetuses had short limb malformations. Samples of fetal umbilical cord blood, amniotic fluid, and/or aborted tissue were collected from all cases. Karyotyping, whole genome sequencing, and targeted next-generation sequencing of skeletal disease-related pathogenic genes were performed, as needed. Blood samples were taken from the parents for verification using Sanger sequencing.ResultsAmong the 30 cases of fetal skeletal dysplasia, two cases were diagnosed with trisomy 18. However, none of these cases were identified with any microdeletions or microreplications associated with skeletal dysplasia. Among the 28 chromosomally normal cases with fetal skeletal dysplasia, 21 cases were detected with mutations in genes related to skeletal diseases. Furthermore, collagen gene mutations were detected in six fetuses with short limb malformations, while heterozygous disease-causing mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were detected in seven fetuses. The remaining fetuses carried mutations in other various genes, including tumor protein p63 (TP63), cholestenol delta-isomerase (EBP), cholinergic receptor nicotinic gamma subunit (CHRNG), filamin B (FLNB), and SRY-box 9 (SOX9). Three compound heterozygous mutations in CHRNG, COL11A2 and SOX9 were carried by phenotypically healthy parents.ConclusionTargeted next-generation sequencing can significantly improve the prenatal diagnoses of fetal skeletal dysplasia, providing parents with more precision medicine, and improved genetic counseling.
| S-EPMC6626426 | biostudies-literature