# Fetal Structural Anomalies and Genetic Etiologies

## Overview

Congenital structural anomalies are detected in approximately 3% of pregnancies on prenatal ultrasound. Genetic etiologies account for a significant proportion: chromosomal abnormalities explain roughly 15-20%, copy number variants add approximately 6% over karyotype, and single-gene disorders contribute an additional 8-20% as revealed by exome sequencing. A systematic approach combining detailed ultrasound phenotyping with tiered genetic testing optimizes diagnostic yield. Prenatal diagnosis of the underlying etiology informs prognosis, recurrence risk, and perinatal management planning.

## Approach to the Fetus with Ultrasound-Detected Anomalies

### Initial Assessment

The evaluation begins with a detailed anatomic survey to determine whether anomalies are isolated or multiple, as multiple anomalies significantly increase the likelihood of a genetic etiology. Assessment includes evaluation for growth restriction, amniotic fluid abnormalities, and placental findings. Review of family history, consanguinity, teratogen exposure, and prior pregnancy outcomes provides essential context. Determining whether the pattern suggests a recognizable syndrome guides subsequent testing.

### Classification of Anomalies

Anomalies are classified into four categories that guide testing strategy and prognosis. Malformations are intrinsic defects in morphogenesis (such as congenital heart defects or neural tube defects). Deformations result from extrinsic mechanical forces acting on normally formed structures (such as clubfoot from oligohydramnios). Disruptions involve breakdown of previously normal structures (such as amniotic band sequence). Dysplasias reflect abnormal organization of cells into tissue (such as skeletal dysplasias).

<image>Flowchart for the systematic evaluation of a fetus with ultrasound-detected structural anomalies, showing the pathway from anomaly detection through detailed anatomic survey, genetic testing selection, and integrated diagnosis</image>

## Tiered Genetic Testing Strategy

### Tier 1: Karyotype and/or Chromosomal Microarray

Karyotype detects aneuploidies, large structural rearrangements, and balanced translocations. Chromosomal microarray (CMA) is the recommended first-line test for fetal structural anomalies per ACOG/SMFM, detecting submicroscopic deletions and duplications not visible on karyotype. CMA provides an additional diagnostic yield of approximately 6% over karyotype for structural anomalies, with higher yield for multiple anomalies (approximately 10%) versus isolated anomalies (3-5%). Both karyotype and CMA should be considered, as CMA cannot detect balanced rearrangements.

### Tier 2: Targeted Molecular Testing

When a specific single-gene disorder is suspected based on ultrasound pattern, targeted testing is appropriate. Examples include FGFR3 for suspected achondroplasia or thanatophoric dysplasia, COL1A1/COL1A2 for suspected osteogenesis imperfecta, DMPK for suspected myotonic dystrophy (hydramnios with decreased fetal movement), CFTR for echogenic bowel with suspected CF, and RASopathy gene panels for increased nuchal translucency with cardiac defect.

### Tier 3: Exome or Genome Sequencing

When karyotype/CMA and targeted testing are nondiagnostic, exome sequencing is offered. Diagnostic yield is approximately 8-10% for isolated anomalies and 15-20% for multiple anomalies after normal karyotype and CMA. Trio analysis (fetus plus both parents) is preferred for optimal variant interpretation. Turnaround time is typically 2-4 weeks for rapid prenatal exome. Challenges include VUS (15-20% of cases), incidental/secondary findings, and incomplete fetal phenotyping that limits genotype-phenotype correlation.

## Anomalies by Organ System and Genetic Associations

### Central Nervous System

Ventriculomegaly (10 mm or greater) is associated with aneuploidies (trisomy 21, 18), 22q11.2 deletion, L1CAM (X-linked hydrocephalus), Walker-Warburg syndrome genes (POMT1/2), and congenital infections. Holoprosencephaly points to trisomy 13, SHH, ZIC2, SIX3, TGIF1, and 13q deletion. Neural tube defects are typically multifactorial but also associated with trisomy 18, 13q deletion, MTHFR polymorphisms, and Meckel-Gruber syndrome genes. Dandy-Walker malformation is linked to trisomy 18, trisomy 13, 6p deletion, Joubert syndrome genes, and 3q deletion. Agenesis of the corpus callosum is associated with Aicardi syndrome (X-linked), L1CAM, chromosomal abnormalities, and nonketotic hyperglycinemia. Microcephaly may reflect MCPH genes, Zika virus, chromosomal causes, or maternal PKU. Lissencephaly involves LIS1, DCX, ARX, and TUBA1A.

### Cardiac

Congenital heart defects are present in approximately 1% of live births with higher detection on prenatal ultrasound. AVSD most commonly associates with trisomy 21, along with 3p25 deletion and 8p23 deletion. Conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch) are strongly associated with 22q11.2 deletion (DiGeorge), the most common microdeletion in CHD. Hypoplastic left heart is linked to Turner syndrome, Jacobsen syndrome (11q23 deletion), and multifactorial causes. Heterotaxy and situs abnormalities involve ZIC3, CFC1, NODAL, and primary ciliary dyskinesia genes. Genetic evaluation is recommended for all prenatally detected CHD, with CMA as a minimum and 22q11.2 FISH specifically for conotruncal defects.

### Renal

Bilateral renal agenesis (Potter sequence) involves RET, ITGA8, and FGF20 and is lethal due to pulmonary hypoplasia. Multicystic dysplastic kidney is often sporadic, though HNF1B is associated with bilateral or syndromic forms. Polycystic kidneys point to PKHD1 (autosomal recessive PKD), PKD1/PKD2 (autosomal dominant, rarely with prenatal onset), or Meckel-Gruber genes. Renal anomalies in syndromic contexts involve HNF1B (renal cysts and diabetes), PAX2 (renal coloboma syndrome), and EYA1/SIX1 (branchio-oto-renal syndrome).

### Skeletal

Short long bones suggest skeletal dysplasias (achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta) or chromosomal abnormalities. Thanatophoric dysplasia (FGFR3) is the most common lethal skeletal dysplasia. Osteogenesis imperfecta involves COL1A1/COL1A2 (autosomal dominant) and recessive forms (CRTAP, LEPRE1, PPIB). Achondroplasia (FGFR3 p.Gly380Arg) may not be apparent until the third trimester. Campomelic dysplasia (SOX9) is notable for sex reversal in 46,XY individuals.

### Gastrointestinal

Omphalocele most commonly associates with trisomy 18, trisomy 13, and Beckwith-Wiedemann syndrome. Gastroschisis is usually sporadic with lower chromosomal risk than omphalocele. Duodenal atresia is associated with trisomy 21 in approximately 30% of cases. Echogenic bowel warrants evaluation for CF (CFTR), trisomy 21, congenital infection, and fetal swallowed blood, with CMA plus CFTR testing recommended. Esophageal atresia/TEF appears in VACTERL association (usually non-genetic), CHARGE syndrome (CHD7), and trisomy 18.

<image>Table of fetal structural anomalies organized by organ system with the most likely genetic etiologies and recommended first-line genetic tests for each anomaly type</image>

| Anomaly/System | Key Genetic Associations | Recommended First-Line Test |
|---|---|---|
| Increased NT (≥3.5 mm) | Trisomy 21/18/13; Turner; Noonan (PTPN11); CHD | CMA + karyotype; RASopathy panel if normal |
| Conotruncal CHD | 22q11.2 deletion (DiGeorge); trisomy 18 | CMA (includes 22q11.2); FISH if rapid result needed |
| AVSD | Trisomy 21; 3p25 deletion; 8p23 deletion | CMA + karyotype |
| Holoprosencephaly | Trisomy 13; SHH, ZIC2, SIX3 | CMA; targeted gene panel if CMA normal |
| Neural tube defect | Multifactorial; trisomy 18; Meckel-Gruber | CMA + AFP/AChE |
| Echogenic bowel | CF (CFTR); trisomy 21; infection | CMA + parental CFTR testing |
| Omphalocele | Trisomy 18/13; BWS (11p15.5) | CMA; methylation studies for BWS |
| Short long bones | Skeletal dysplasias (FGFR3, COL1A1/A2); trisomy 21 | CMA; targeted gene testing based on pattern |
| Bilateral renal agenesis | RET, ITGA8, FGF20 | CMA; exome if CMA normal |
| Non-immune hydrops | 45,X; alpha-thal; LSDs; Noonan; CDG | CMA + karyotype; metabolic screen; exome |

### Increased Nuchal Translucency (NT)

NT of 3.5 mm or greater (or above the 99th percentile) is significantly associated with genetic conditions. Aneuploidies include trisomy 21, 18, 13, and Turner syndrome (45,X, often with cystic hygroma). Noonan syndrome and other RASopathies (PTPN11, SOS1, RAF1, RIT1, KRAS) are important non-chromosomal causes. Congenital heart defects occur even with normal karyotype/CMA. Other associations include Smith-Lemli-Opitz syndrome (DHCR7), congenital diaphragmatic hernia, and skeletal dysplasia. Increased NT with normal karyotype/CMA should prompt consideration of a RASopathy panel or exome sequencing.

### Hydrops Fetalis

Non-immune hydrops (NIHF) accounts for over 80% of hydrops cases and has diverse genetic etiologies. Chromosomal causes include Turner syndrome (45,X) and trisomies 21, 18, and 13. Hematologic causes encompass alpha-thalassemia (Hb Bart's from HBA1/HBA2 deletions) and RBC enzyme defects. Metabolic causes include lysosomal storage diseases (Gaucher type 2, Niemann-Pick, mucopolysaccharidoses, GM1 gangliosidosis) and congenital disorders of glycosylation. Cardiac causes include structural defects, arrhythmias, and cardiomyopathy. Lymphatic causes include Noonan syndrome. Exome sequencing yield in NIHF is approximately 15-29%.

## Integration of Imaging and Molecular Results

### Concordance Assessment

The essential question is whether molecular findings explain the observed anomalies. Genotype-phenotype correlation is critical: finding a VUS in a gene associated with features different from those observed does not constitute a diagnosis. Multidisciplinary discussion involving MFM, genetics, and pediatric subspecialists improves diagnostic accuracy.

### Prognostication

Molecular diagnosis may clarify prognosis when ultrasound findings alone are ambiguous. For example, short femurs with molecular confirmation of thanatophoric dysplasia (lethal) versus achondroplasia (non-lethal) carry vastly different implications. Similarly, echogenic kidneys with PKHD1 mutations (potentially severe) versus HNF1B deletion (variable renal phenotype with diabetes risk) require different counseling.

### Limitations of Prenatal Phenotyping

The fetal phenotype is incomplete, as many features only become apparent postnatally. Ultrasound sensitivity varies by gestational age, maternal habitus, and fetal position. Serial imaging may reveal evolving findings, and genetic results may identify conditions not yet fully manifest on ultrasound.

<image>Case example showing integration of prenatal ultrasound findings (increased NT, cardiac defect, polyhydramnios) with genetic testing results (RASopathy gene panel showing PTPN11 pathogenic variant) leading to a diagnosis of Noonan syndrome with counseling about postnatal management</image>

## Clinical Pearls

CMA is the recommended first-tier test for any fetal structural anomaly, providing approximately 6% additional diagnostic yield over karyotype. The 22q11.2 deletion is the most common microdeletion causing congenital heart disease, and FISH or CMA should be performed for all conotruncal defects. Echogenic bowel warrants CF carrier testing of both parents and CMA of the fetus, as the differential includes CF, trisomy 21, infection, and swallowed blood. Non-immune hydrops has a genetic etiology in over 50% of cases, and comprehensive genetic evaluation including metabolic and exome testing should be pursued. Prenatal exome sequencing has the highest yield when multiple anomalies are present and karyotype/CMA are normal. Increased NT is not specific to chromosomal abnormalities -- Noonan syndrome (RASopathies) is a major genetic cause of increased NT with normal karyotype. Karyotype should always be obtained in addition to CMA for prenatally detected anomalies, as balanced rearrangements relevant for recurrence risk are missed by CMA. A "normal" genetic workup does not exclude a genetic etiology, as approximately 50% of fetuses with multiple anomalies remain undiagnosed even after exome sequencing.

## References

- Wapner RJ, Martin CL, Levy B, et al. "Chromosomal microarray versus karyotyping for prenatal diagnosis." *New England Journal of Medicine*. 2012;367(23):2175-2184.
- Lord J, McMullan DJ, Eberhardt RY, et al. "Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study." *Lancet*. 2019;393(10173):747-757.
- Petrovski S, Aggarwal V, Giordano JL, et al. "Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study." *Lancet*. 2019;393(10173):758-767.
- ACOG Practice Bulletin No. 162: "Prenatal diagnostic testing for genetic disorders." *Obstetrics & Gynecology*. 2016;127(5):e108-e122.
- Sparks TN, Lianoglou BR, Adami RR, et al. "Exome sequencing for prenatal diagnosis in nonimmune hydrops fetalis." *New England Journal of Medicine*. 2020;383(18):1746-1756.