Fetal Care Research Highlights Power of Genetics

Researchers from Cincinnati Children’s Fetal Care Center presented four posters at the 28th annual meeting of the International Society for Prenatal Diagnosis (ISPD) in July.

The findings show how certain types of genetic testing, sequencing and phenotyping can help clinicians diagnose atypical conditions, determine prenatal and postnatal care, and provide guidance to families about what to expect.

Cincinnati Children’s co-authors included genetic counselors Jacquelynn Berton, MS, CGC; Leandra Tolusso, MS, LGC; Kimberly Widmeyer, MS, CGC, and Beatrix Wong, MS, LGC; researchers Stephanie Balow, PhD; Nicole A. Horton, BS; Ethan Lorence, MS, and additional team members.

Recognizing Co-Occurring Genetic Conditions

The presence of multiple diagnoses can complicate clinical presentation and phenotype classification. In “Case Report: Concomitant Skeletal Dysplasia and Overgrowth Syndromes,” Berton and Wong share the case of a male fetus referred after an abnormal anatomy ultrasound.

The fetus presented with diagnoses of short-rib thoracic dysplasia (SRTD3), Sotos syndrome and Malan syndrome—and a possible fourth diagnosis of aggrecan-related (ACAN gene) short stature.

Each diagnosis is rare. Three at the same time made for difficult counseling on prognosis as well as pre- and postnatal treatment options. Genetic testing provided some guidance. But the multiple syndromes put the neonate at increased risk for complications.

The team concluded the possibility of co-occurring genetic conditions should be considered in fetuses with atypical findings.

Studying FISH Genetic Testing for Fetal Surgery Eligibility

No universal guidelines exist for fetal surgery eligibility. Decisions are made on an institutional basis. At Cincinnati Children’s, surgery eligibility depends on many factors including genetic testing and number of birth defects.

In a retrospective chart study, Lorence, Wong and other researchers investigated whether fluorescence in situ hybridization (FISH) genetic testing provides additional diagnostic information for fetal surgery eligibility.

Findings from “Utility of FISH as a fetal surgery eligibility criterion for isolated congenital anomalies” include:

• Microarray provided a higher diagnostic yield than FISH. Microarray may be a more informative genetic test for surgical candidacy.
• FISH was concordant with screening results in 100% of pregnancies whose screening workup suggested a fetus at low risk for trisomy 21, trisomy 18, trisomy 13 and sex chromosome aneuploidies.
• FISH did not provide additional information compared to comprehensive imaging and cell-free DNA testing.
• FISH’s need for invasive fetal DNA collection introduces additional risk to the pregnancy.

Future research may investigate whether all aneuploid fetuses should be excluded from surgery based on their aneuploidy (abnormal number of chromosomes). Aneuploid fetuses usually have multiple congenital anomalies.

Improving Diagnostic Work-up for Fetuses with Short Long Bones

Changes to the short stature homeobox (SHOX) gene can cause short stature and short fetal long bones. In most cases this is caused by the deletion of the coding region. However, more than a third of cases are caused by downstream SHOX enhancer region deletions that leave the coding sequencing intact. In their poster, “SHOX enhancer region deletion: A cause of short fetal long bones that may be missed by exome-based sequencing,” Balow and Tolusso aim to increase prenatal providers’ awareness of this etiology.

Conclusions include:

• Enhancer region changes can be missed by sequencing or copy number variant analysis methods that focus on SHOX exons. Enhancer regions sit outside the exonic area.
• Analysis of non-coding DNA surrounding SHOX should be considered in diagnostic workup.

Understanding Differences in Prenatal and Postnatal Phenotypes

A study of neonates with congenital anomalies prenatally evaluated at Cincinnati Children’s finds limits to prenatal imaging’s ability to capture comprehensive fetal phenotypes. Recognizing this limitation can improve prenatal genetic testing.

In "Differences in prenatal and postnatal phenotypes in patients with congenital anomalies and known genetic diagnoses,” Horton, Widmeyer and Tolusso reviewed records for babies who received neonatal inpatient care between July 2018 and December 2022.

• Fetuses with anomalies should be evaluated at multiple times before and after birth for comprehensive phenotyping.
• Chromosomal microarray testing is not enough to evaluate congenital anomalies. Sequencing should be offered with comprehensive prenatal genetic testing.
• Clinicians and labs should pay attention to phenotypes often missed by imaging and refrain from over-emphasizing the absence of phenotypes when interpreting results.

(Published October 2024)