A fetal diagnosis of LRP2-related Donnai-Barrow syndrome through prenatal genome sequencing
Prenatal Genetics
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Primary Categories:
- Genetic Counseling
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Secondary Categories:
- Genetic Counseling
Introduction
We present a unique case in which prenatal genome sequencing (GS) led to a suspected fetal diagnosis of Donnai-Barrow syndrome (DBS) (OMIM: 222448). Fewer than 100 cases of DBS, often occurring within a small number of consanguineous families, have been reported in the literature. Variants in LRP2 (NM_004525.3) are specifically associated with DBS. Individuals who are homozygous or compound heterozygous for pathogenic or likely pathogenic (P/LP) variants in LRP2 may present with craniofacial abnormalities, agenesis of the corpus callosum, omphalocele, diaphragmatic hernia, intellectual disability and renal disease, while individuals heterozygous for P/LP variants are not known to be at risk for any symptoms, such as renal dysfunction. The diagnosis of DBS in this fetus from a non-consanguineous pairing bears significance in that the diagnosis is supported by GS identification of two novel variants of uncertain clinical significance (VUS) in trans that may have eluded detection through exome sequencing.
Case Presentation
A 38-year-old G6P2 pregnant patient with chronic hypertension and a history of poor obstetric outcomes was referred to our department for ultrasound at 24 1/7 weeks of gestation for further assessment of previous findings of abnormal fetal facial profile (FFP) and fetal growth restriction (FGR). The patient had a low risk prenatal cell-free DNA screening (cfDNA) result and a screen positive MS AFP deemed uninterpretable due to incorrect dating.
Diagnostic Workup
Our ultrasound confirmed an abnormal FFP suggestive of midface hypoplasia and FGR with an estimated fetal weight at the first percentile, abdominal circumference at the fourth percentile, and head circumference below the first percentile. Umbilical artery Doppler readings were normal. Additional ultrasound findings included an intracardiac echogenic focus and a hypoplastic cavum septum pellucidum. Subsequent amniocentesis yielded normal results for amniotic fluid alpha-fetoprotein, fetal karyotype, and fetal chromosomal microarray. PCR on amniotic fluid for cytomegalovirus, toxoplasmosis, and parvovirus DNA all returned negative.
Treatment and Management
A fetal MRI at 27 1/7 weeks of gestation noted agenesis of the corpus callosum and an absent cavum septum pellucidum. Trio genome sequencing (GS) with masking of incidental findings was ordered. Six weeks after amniocentesis was performed, the patient suffered an intrauterine fetal demise secondary to pre-eclampsia.
Outcome and Follow-Up
The trio GS results reported two variants in LRP2, one paternally-derived c.770-4dupA intronic VUS and one maternally-derived c.13847C>T (p.Ser4616Leu) VUS, suggestive of a fetal diagnosis of Donnai-Barrow syndrome. Since a 25% risk for DBS to couple’s offspring is suspected, the couple was referred to medical genetics for a preconception consult and to an IVF clinic for consideration of IVF with preimplantation genetic testing for monogenic disorders (PGT-M) for future pregnancies. Trio GS also detected heterozygosity for a paternally-derived pathogenic variant in VPS13B (NM_017890.4) associated with autosomal recessive Cohen syndrome (OMIM: 216550). Carrier screening through VPS13B sequencing and deletion/duplication analysis was offered to the patient to assess the risk for Cohen syndrome to couple’s offspring.
Discussion
Prenatal GS may report uncertain results confounding both patients and clinicians. Identification of a VUS may delay a diagnosis and increase anxiety. Appropriate pretest counseling can mitigate the potential negative impact of this uncertainty. Cases like this one highlight the importance of clinical interpretation of VUS.
Conclusion
This case involves GS identification of fetal compound heterozygosity for two VUSs in LRP2 associated with autosomal recessive Donnai-Barrow syndrome that has features consistent with the fetal phenotype. The variant classification introduces a level of uncertainty into the recurrence risk assessment that may increase anxiety and complicate PGT and prenatal diagnostic testing options. An evaluation of the clinical utility of a comprehensive genetic testing approach involving an inclusive reflex to gene-specific RNA sequencing targeted analysis as part of GS for these cases is warranted.
We present a unique case in which prenatal genome sequencing (GS) led to a suspected fetal diagnosis of Donnai-Barrow syndrome (DBS) (OMIM: 222448). Fewer than 100 cases of DBS, often occurring within a small number of consanguineous families, have been reported in the literature. Variants in LRP2 (NM_004525.3) are specifically associated with DBS. Individuals who are homozygous or compound heterozygous for pathogenic or likely pathogenic (P/LP) variants in LRP2 may present with craniofacial abnormalities, agenesis of the corpus callosum, omphalocele, diaphragmatic hernia, intellectual disability and renal disease, while individuals heterozygous for P/LP variants are not known to be at risk for any symptoms, such as renal dysfunction. The diagnosis of DBS in this fetus from a non-consanguineous pairing bears significance in that the diagnosis is supported by GS identification of two novel variants of uncertain clinical significance (VUS) in trans that may have eluded detection through exome sequencing.
Case Presentation
A 38-year-old G6P2 pregnant patient with chronic hypertension and a history of poor obstetric outcomes was referred to our department for ultrasound at 24 1/7 weeks of gestation for further assessment of previous findings of abnormal fetal facial profile (FFP) and fetal growth restriction (FGR). The patient had a low risk prenatal cell-free DNA screening (cfDNA) result and a screen positive MS AFP deemed uninterpretable due to incorrect dating.
Diagnostic Workup
Our ultrasound confirmed an abnormal FFP suggestive of midface hypoplasia and FGR with an estimated fetal weight at the first percentile, abdominal circumference at the fourth percentile, and head circumference below the first percentile. Umbilical artery Doppler readings were normal. Additional ultrasound findings included an intracardiac echogenic focus and a hypoplastic cavum septum pellucidum. Subsequent amniocentesis yielded normal results for amniotic fluid alpha-fetoprotein, fetal karyotype, and fetal chromosomal microarray. PCR on amniotic fluid for cytomegalovirus, toxoplasmosis, and parvovirus DNA all returned negative.
Treatment and Management
A fetal MRI at 27 1/7 weeks of gestation noted agenesis of the corpus callosum and an absent cavum septum pellucidum. Trio genome sequencing (GS) with masking of incidental findings was ordered. Six weeks after amniocentesis was performed, the patient suffered an intrauterine fetal demise secondary to pre-eclampsia.
Outcome and Follow-Up
The trio GS results reported two variants in LRP2, one paternally-derived c.770-4dupA intronic VUS and one maternally-derived c.13847C>T (p.Ser4616Leu) VUS, suggestive of a fetal diagnosis of Donnai-Barrow syndrome. Since a 25% risk for DBS to couple’s offspring is suspected, the couple was referred to medical genetics for a preconception consult and to an IVF clinic for consideration of IVF with preimplantation genetic testing for monogenic disorders (PGT-M) for future pregnancies. Trio GS also detected heterozygosity for a paternally-derived pathogenic variant in VPS13B (NM_017890.4) associated with autosomal recessive Cohen syndrome (OMIM: 216550). Carrier screening through VPS13B sequencing and deletion/duplication analysis was offered to the patient to assess the risk for Cohen syndrome to couple’s offspring.
Discussion
Prenatal GS may report uncertain results confounding both patients and clinicians. Identification of a VUS may delay a diagnosis and increase anxiety. Appropriate pretest counseling can mitigate the potential negative impact of this uncertainty. Cases like this one highlight the importance of clinical interpretation of VUS.
Conclusion
This case involves GS identification of fetal compound heterozygosity for two VUSs in LRP2 associated with autosomal recessive Donnai-Barrow syndrome that has features consistent with the fetal phenotype. The variant classification introduces a level of uncertainty into the recurrence risk assessment that may increase anxiety and complicate PGT and prenatal diagnostic testing options. An evaluation of the clinical utility of a comprehensive genetic testing approach involving an inclusive reflex to gene-specific RNA sequencing targeted analysis as part of GS for these cases is warranted.
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