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A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review.

ABSTRACT: Non-immune hydrops fetalis (NIHF) indicates the risk for stillbirth. Although the causes vary and most NIHFs have no identifiable cause, recent advances in exome sequencing have increased diagnostic rates. We report a case of NIHF that developed into a giant cystic hygroma complicated by maternal mirror syndrome. Trio-based exome sequencing showed a de novo heterozygous missense variant in the RIT1 (NM_006912: c.246 T > G [p.F82L]). The RIT1 variants are known causative variants of Noonan syndrome (NS; OMIM #163950). The location of the RIT1 variants in the previously reported NS cases with NIHF or/and maternal mirror syndrome was mainly in the switch II region, including the present case. While a further accumulation of cases is needed, exome sequencing, which can identify the variant type in detail, might help predict the phenotype and severity of NIHF.

SUBMITTER: Tano S

PROVIDER: S-EPMC9579035 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review.

Tano Sho S Kotani Tomomi T Yoshihara Masato M Nakamura Noriyuki N Matsuo Seiko S Ushida Takafumi T Imai Kenji K Ito Miharu M Oka Yasuyoshi Y Sato Emi E Hayashi Shin S Ogi Tomoo T Kajiyama Hiroaki H

Molecular genetics and metabolism reports 20221014

Non-immune hydrops fetalis (NIHF) indicates the risk for stillbirth. Although the causes vary and most NIHFs have no identifiable cause, recent advances in exome sequencing have increased diagnostic rates. We report a case of NIHF that developed into a giant cystic hygroma complicated by maternal mirror syndrome. Trio-based exome sequencing showed a de novo heterozygous missense variant in the <i>RIT1</i> (NM_006912: c.246 T > G [p.F82L]). The <i>RIT1</i> variants are known causative variants of ...[more]

PMID: 36274670

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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.).

Project description:BackgroundNext-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known.ObjectiveWe compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis.Study designThis was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes.ResultsExome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing.ConclusionThe broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.

Dataset Information

A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review.

Publications

A case of non-immune hydrops fetalis with maternal mirror syndrome diagnosed by trio-based exome sequencing: An autopsy case report and literature review.

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