Is Exome Sequencing Helpful in the Diagnosis of Nonimmune Hydrops?
BACKGROUND AND PURPOSE:
Single-gene disorders are included in the differential for nonimmune hydrops fetalis (NIHF)
Sparks et al. (NEJM, 2020) examined the diagnostic yield of exome sequencing for single-gene disorders in unexplained NIHF
Consecutive unexplained cases of NIHF
Definition of NIHF: Following findings alone or in combination
Presence of fetal ascites | Pleural or pericardial effusions | Skin edema | Cystic hygroma | Increased nuchal translucency
Classification of genetic variants: Based upon criteria of the ACMG
Diagnostic yield of exome sequencing for detecting pathogenic or likely pathogenic genetic variants
Percentage of cases associated with specific genetic disorders
The proportion of variants that were inherited
127 cases included
Cases with diagnostic genetic variants: 29% (37 cases)
RAS–MAPK cell-signaling pathway (RASopathies such as Noonan syndrome): 30% of genetic diagnoses
Inborn errors of metabolism and musculoskeletal disorders: 11% each
Lymphatic, neurodevelopmental, cardiovascular, and hematologic disorders: 8% each
Prognoses ranged from a relatively mild outcome to death during the perinatal period
Cases with diagnostic variants that were autosomal dominant: 68% (25 of 37)
De novo: 88%
Cases with diagnostic variants that were autosomal recessive: 27% (10 of 37)
De novo: 5%
There was also 1 inherited X-linked recessive case, and 1 case of uncertain inheritance
12 additional cases had potentially diagnostic variants
Exome sequencing identified diagnostic genetic variants in approximately one third of unexplained NIHF cases
The authors conclude
These data support the use of exome sequencing for NIHF cases with nondiagnostic results of chromosomal microarray analysis or karyotype analysis in order to inform prognosis, establish recurrence risk, and direct prenatal and postnatal clinical care
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