A Clinical Practice Guideline for Genetic Testing in Perinatal Demise: Enhancing Diagnosis Through Multidisciplinary Collaboration
Clinical Genetics and Therapeutics
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Primary Categories:
- Health services and Implementation
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Secondary Categories:
- Health services and Implementation
Introduction:
Introduction: Genetic abnormalities significantly contribute to recurrent pregnancy loss, intrauterine fetal demise, stillbirth, neonatal critical illness, and early neonatal death. Despite the high prevalence of genetic disease in these cases, barriers to genetic testing persist, including family feelings regarding fetal risk of prenatal testing, limited postnatal sample collection windows, complex billing practices, psychosocial concerns, and unclear responsibilities among clinical teams. A genetic diagnosis from fetal or neonatal tissue is crucial for assessing recurrence risk and can provide closure to families.
Methods:
Methods: In response to a need for improved communication between prenatal and postnatal genetic services for high-risk cases, a multidisciplinary team developed a clinical practice guideline (CPG) for perinatal demise genetic testing. Team members represented prenatal genetic counseling, pediatric genetics, neonatology, obstetrics, health information technology, billing, molecular diagnostics, clinical genomics, pathology, palliative care, decedent affairs, ethics, and legal. The CPG includes workflows, documentation, test selection guidance, and directions to necessary facilities. Cases are logged in a REDCap database for tracking and iterative CPG improvement.
Results:
Results: The CPG improved access to genetic testing, enabling diagnoses that would otherwise have been missed. Case 1: An Amish monochorionic-diamniotic twin presented with prenatal ultrasound findings concerning for an imperforate anus, tracheoesophageal fistula, renal failure, open neural tube defect, and pulmonary hypoplasia. Exome sequencing identified a de novo likely pathogenic CHD4 variant (c.3004G>A, p.G1002S) associated with autosomal dominant Sifrim-Hitz-Weiss Syndrome (SIHIWES) and a heterozygous likely pathogenic ANKS6 variant (c.1381C>T, p.R461*). Both parents were carriers of the ANKS6 variant. Family testing revealed that the twin sister had a less severe expression of SIHIWES, and siblings of the proband were diagnosed with the autosomal recessive ANKS6-associated disorder. The CPG facilitated timely communication between the clinical teams, pre-delivery consent, umbilical cord sampling, a testing shift from CMA to diagnostic trio exome, and uncovered a second diagnosis in family members. Case 2: A female fetus was diagnosed on ultrasound with sacral agenesis, syringomyelia, brachycephaly, and other congenital anomalies. CMA via amniocentesis revealed a paternally inherited 75kb deletion at 14q22.2, including the BMP4 gene. Larger deletions of this region cause autosomal dominant Frias Syndrome (short stature, facial and ocular anomalies, and congenital limb anomalies). BMP4 haploinsufficiency typically causes overlapping but milder features than Frias Syndrome. Exome sequencing initiated at delivery identified a de novo CTCF variant of uncertain significance (c.1052T>A, p.F351Y), possibly explaining the more severe presentation. The CPG enabled communication between prenatal genetic counseling, maternal-fetal medicine, obstetrics, and pediatric genetics, allowed for CMA interpretation before delivery, collection of fetal samples, and trio exome sequencing, which identified the de novo variant. Case 3: A newborn male was prenatally diagnosed with fetal growth restriction, absent cavum septum pellucidum, possible agenesis of the corpus callosum, Dandy-Walker malformation, and other congenital anomalies. Postnatal findings included renal cysts, retinochoroidal colobomas, and dysmorphic features. A CMA was sent while clinically stable. As his condition declined, exome sequencing was initiated before care was withdrawn, which identified a de novo likely pathogenic ACTB (c.628C>T, p.R210C) variant linked to Baraitser-Winter Syndrome 1. The CPG facilitated efficient communication in an evolving clinical and family scenario, enabled testing beyond a CMA, and ensured exome sequencing before the patient’s passing. Identifying the de novo variant allowed for a more accurate recurrence risk assessment for the family.
Conclusion:
Conclusions: This multidisciplinary CPG has enabled enhanced timely access to genetic testing for families facing perinatal demise, allowing for the identification of complex genetic diagnoses, dual diagnoses, and informing recurrence risk assessments for families who choose to undergo genetic testing. The CPG provides an essential framework for continued collaboration and refinement for patients with congenital anomalies and associated perinatal loss.
Introduction: Genetic abnormalities significantly contribute to recurrent pregnancy loss, intrauterine fetal demise, stillbirth, neonatal critical illness, and early neonatal death. Despite the high prevalence of genetic disease in these cases, barriers to genetic testing persist, including family feelings regarding fetal risk of prenatal testing, limited postnatal sample collection windows, complex billing practices, psychosocial concerns, and unclear responsibilities among clinical teams. A genetic diagnosis from fetal or neonatal tissue is crucial for assessing recurrence risk and can provide closure to families.
Methods:
Methods: In response to a need for improved communication between prenatal and postnatal genetic services for high-risk cases, a multidisciplinary team developed a clinical practice guideline (CPG) for perinatal demise genetic testing. Team members represented prenatal genetic counseling, pediatric genetics, neonatology, obstetrics, health information technology, billing, molecular diagnostics, clinical genomics, pathology, palliative care, decedent affairs, ethics, and legal. The CPG includes workflows, documentation, test selection guidance, and directions to necessary facilities. Cases are logged in a REDCap database for tracking and iterative CPG improvement.
Results:
Results: The CPG improved access to genetic testing, enabling diagnoses that would otherwise have been missed. Case 1: An Amish monochorionic-diamniotic twin presented with prenatal ultrasound findings concerning for an imperforate anus, tracheoesophageal fistula, renal failure, open neural tube defect, and pulmonary hypoplasia. Exome sequencing identified a de novo likely pathogenic CHD4 variant (c.3004G>A, p.G1002S) associated with autosomal dominant Sifrim-Hitz-Weiss Syndrome (SIHIWES) and a heterozygous likely pathogenic ANKS6 variant (c.1381C>T, p.R461*). Both parents were carriers of the ANKS6 variant. Family testing revealed that the twin sister had a less severe expression of SIHIWES, and siblings of the proband were diagnosed with the autosomal recessive ANKS6-associated disorder. The CPG facilitated timely communication between the clinical teams, pre-delivery consent, umbilical cord sampling, a testing shift from CMA to diagnostic trio exome, and uncovered a second diagnosis in family members. Case 2: A female fetus was diagnosed on ultrasound with sacral agenesis, syringomyelia, brachycephaly, and other congenital anomalies. CMA via amniocentesis revealed a paternally inherited 75kb deletion at 14q22.2, including the BMP4 gene. Larger deletions of this region cause autosomal dominant Frias Syndrome (short stature, facial and ocular anomalies, and congenital limb anomalies). BMP4 haploinsufficiency typically causes overlapping but milder features than Frias Syndrome. Exome sequencing initiated at delivery identified a de novo CTCF variant of uncertain significance (c.1052T>A, p.F351Y), possibly explaining the more severe presentation. The CPG enabled communication between prenatal genetic counseling, maternal-fetal medicine, obstetrics, and pediatric genetics, allowed for CMA interpretation before delivery, collection of fetal samples, and trio exome sequencing, which identified the de novo variant. Case 3: A newborn male was prenatally diagnosed with fetal growth restriction, absent cavum septum pellucidum, possible agenesis of the corpus callosum, Dandy-Walker malformation, and other congenital anomalies. Postnatal findings included renal cysts, retinochoroidal colobomas, and dysmorphic features. A CMA was sent while clinically stable. As his condition declined, exome sequencing was initiated before care was withdrawn, which identified a de novo likely pathogenic ACTB (c.628C>T, p.R210C) variant linked to Baraitser-Winter Syndrome 1. The CPG facilitated efficient communication in an evolving clinical and family scenario, enabled testing beyond a CMA, and ensured exome sequencing before the patient’s passing. Identifying the de novo variant allowed for a more accurate recurrence risk assessment for the family.
Conclusion:
Conclusions: This multidisciplinary CPG has enabled enhanced timely access to genetic testing for families facing perinatal demise, allowing for the identification of complex genetic diagnoses, dual diagnoses, and informing recurrence risk assessments for families who choose to undergo genetic testing. The CPG provides an essential framework for continued collaboration and refinement for patients with congenital anomalies and associated perinatal loss.