Introduction
Prenatal cell-free DNA screening (cfDNA) analyzes circulating DNA in maternal plasma and is most often ordered to assess the fetal risk for common aneuploidies (cfDNA-A). cfDNA for autosomal dominant and recessive monogenic disorders (cfDNA-M), also known as single-gene cfDNA, is less frequently used and is currently not recommended for routine general population screening based on insufficient clinical validity. cfDNA-M has been shown to facilitate early detection of fetal conditions, particularly in the context of a family history or fetal structural anomalies on ultrasound. We present a case of a patient brought to our attention after routine cfDNA-M returned positive for the c.487 G>A p.(G163S) novel variant in exon 11 of COL1A2 (HGNC: 2198).

 

Case Presentation
A 34-year-old G1P0 patient presented at 22 weeks 5 days gestation for amniocentesis with fetal single-gene diagnostic testing because of an abnormal cfDNA-M result related to COL1A2. COL1A2 is associated with a broad spectrum of autosomal dominant and autosomal recessive conditions that affect connective and skeletal tissue. COL1A2 disorders include multiple different phenotypes of autosomal dominant (MedGen UID: 45246) and autosomal recessive (PMID: 29572562) osteogenesis imperfecta (OI) and multiple different phenotypes of Ehlers-Danlos syndrome (EDS) (OMIM 130090) including autosomal dominant arthrochalasia EDS (EDS VII) (OMIM 130060; MedGen UID 78662), and autosomal recessive cardiac-valvular EDS (cv-EDS) (OMIM 225320; MedGen UID 347359). Patient’s cfDNA-A returned low risk. Patient’s cfDNA-M returned positive for a novel likely pathogenic variant (LPV) in COL1A2 at a level that is consistent with a suspected maternal variant, suggesting a 50% risk to the fetus for variant inheritance.

 

Diagnostic Workup
Patient denied a personal or family history of features or conditions associated with COL1A2 pathogenic variants. Although reported as an LPV, the variant was classified by two other laboratories as a variant of uncertain significance (VUS) complicating the options for fetal diagnostic testing. Detailed fetal anatomic survey at 22 weeks 3 days returned negative for fetal anomalies with a normal EFW at the 69%-ile. Maternal and fetal targeted variant analysis were ordered since the request for COL1A2 full gene sequence analysis with deletion/duplication testing was rejected by the laboratory based on variant classification. Fetal and maternal targeted variant analysis performed at 23 weeks 3 days identified that both the patient and fetus have the c.487 G>A COL1A2 variant and patient was referred to medical genetics. COL1A2 sequence analysis with deletion/duplication testing on the reported father of the pregnancy returned negative, reducing the fetal risk for COL1A2-related autosomal recessive disorders. Patient’s clinical genetics evaluation reported the following physical findings: light, brown irides with blue-grey tinted sclerae, slight exophthalmos, atypically soft skin with striae, mildly high arched palate, some atrophic scarring at points of articulation, and a negative Beighton Score of 1. COL1A2 full gene sequencing analysis on the patient through medical genetics returned positive for the known variant and negative for other pathogenic/likely pathogenic variants excluding a COL1A2-related autosomal recessive condition for the patient.

 

Treatment and Management
Patient’s personal and fetal echocardiograms returned within normal limits.

 

Outcome and Follow-Up
Postnatal evaluation of the baby by pediatric genetics was recommended. Postpartum skeletal survey for the patient was recommended by medical genetics. At 38 weeks 1 day there was a NSVD of a healthy baby assigned male at birth with an Apgar score of 9.

Discussion
This case in which cfDNA-M led to identification of a maternal and fetal predisposition to or clinical diagnosis of a COL1A2-related disorder, highlights the complexities and benefits associated with performing routine cfDNA-M and with the clinical interpretation of variant classification.

Conclusion
The inevitable eventual launch of cfDNA of the fetal exome necessitates that we continue examining the clinical utility of cfDNA-M and the psychosocial impact on this patient population.