Expanding the Prenatal and Postnatal Phenotype of 1q21.1 Duplication: A Case Report
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Recurrent duplications involving chromosome 1q21.1 have been associated with high phenotypic diversity, including a normal phenotype. These microduplications display variable expressivity and incomplete penetrance, even among family members with the same copy number variant (CNV). Affected individuals have a wide spectrum of features, including cardiac defects, brain anomalies, intellectual disability, developmental delay, autism, eye abnormalities, macrocephaly, facial dysmorphism, psychiatric conditions, and behavioral disturbances. Previously described prenatal features include fetal ventriculomegaly, nasal bone aplasia, cardiac anomalies, duodenal atresia, and micrognathia. We describe a prenatally diagnosed case of 1q21.1 duplication with findings not previously reported.
Case Presentation
A 36-year-old G6P2032 presented at 20 weeks’ gestation for Maternal Fetal Medicine consultation for fetal hydrocephalus. The patient’s medical history included migraines with aura and obesity. Her only medication was a prenatal vitamin. The patient and her partner were nonconsanguineous. The patient reported Caucasian ancestry while her partner reported German, Irish, and Armenian ancestry. Family history and social history were nonsignificant.
Prenatal cfDNA screening previously performed was low risk for trisomies 21, 18, and 13, monosomy X, and 22q11.2 deletion syndrome. Carrier screening for 27 autosomal recessive and X-linked conditions was also low risk.
Diagnostic Workup
Detailed ultrasound demonstrated severe bilateral ventriculomegaly, macrocephaly, absent corpus callosum (CC), absent cavum septum pellucidum (CSP), a dilated 3rd ventricle, and a small cerebellum. The remaining anatomic survey appeared normal. A fetal MRI was ordered and showed an incomplete CSP anteriorly. It was otherwise consistent with ultrasound findings. Fetal echocardiogram was normal.
The patient was referred to genetic counseling and elected for an amniocentesis at 21 weeks’ gestation. FISH was normal for chromosomes 13, 18, 21, X and Y. Karyotype was normal: 46,XY. Amniotic fluid PCR for cytomegalovirus, parvovirus and toxoplasmosis returned negative, and amniotic fluid AFP was normal. Chromosomal microarray analysis (CMA) revealed a 1.73 MB distal duplication of 1q21.1>q21.2: arr[hg19] 1q21.1q21.2(146,105,171-147,830,903) x3. This region includes 10 OMIM genes (NBPF14, PRKAB2, CHD1L, FMO5, BCL9, ACP6, GJA5, GJA8, GPR89B, NBPF11). Exome sequencing was negative except for the duplication noted on CMA.
Treatment and Management
The patient was counseled on all management options and elected for continuation of pregnancy. She was subsequently diagnosed with gestational diabetes and anemia requiring Metformin and IV iron infusions. She underwent neonatology and pediatric neurosurgery consultations antenatally. Serial growth ultrasounds and antenatal testing were performed revealing polyhydramnios at 28 weeks and large for gestational age (LGA) fetus at 31 weeks that persisted. Head circumference and biparietal diameter measured greater than the 95th percentile.
Outcome and Follow-Up
The patient underwent an uncomplicated Cesarean section at 36 weeks for decreased fetal movement, preterm labor, and breech presentation. A male infant was delivered with birth weight 4340 grams and APGARS 2, 6, and 7 at 1, 5, and 10 minutes, respectively. Postnatal findings included macrocephaly with frontal bossing, a mildly dilated ascending aorta, an anorectal malformation, and disordered eye movements. Imaging confirmed marked hydrocephalus with CC hypoplasia, absence of the CSP, and an arachnoid cyst. The infant underwent subgaleal shunt placement and diverting colostomy on day 2 of life, third ventriculostomy at 1 week of life, ventriculoperitoneal shunt placement at 2 weeks, and anorectoplasty at 5 months. He has developmental delays and is enrolled in Early Intervention.
Discussion
To our knowledge, this is the first case reporting absent CSP and anorectal malformation in an individual with 1q21.1 duplication. Additionally, while previous cases reported fetal ventriculomegaly, none were reported to be as severe as noted here. This case highlights the high phenotypic variability of 1q21.1 duplication and resulting challenges posed in genetic counseling in the prenatal setting.
Conclusion
Further studies are needed to determine the function of the genes implicated in this duplication and the molecular mechanisms underlying these novel findings.
Recurrent duplications involving chromosome 1q21.1 have been associated with high phenotypic diversity, including a normal phenotype. These microduplications display variable expressivity and incomplete penetrance, even among family members with the same copy number variant (CNV). Affected individuals have a wide spectrum of features, including cardiac defects, brain anomalies, intellectual disability, developmental delay, autism, eye abnormalities, macrocephaly, facial dysmorphism, psychiatric conditions, and behavioral disturbances. Previously described prenatal features include fetal ventriculomegaly, nasal bone aplasia, cardiac anomalies, duodenal atresia, and micrognathia. We describe a prenatally diagnosed case of 1q21.1 duplication with findings not previously reported.
Case Presentation
A 36-year-old G6P2032 presented at 20 weeks’ gestation for Maternal Fetal Medicine consultation for fetal hydrocephalus. The patient’s medical history included migraines with aura and obesity. Her only medication was a prenatal vitamin. The patient and her partner were nonconsanguineous. The patient reported Caucasian ancestry while her partner reported German, Irish, and Armenian ancestry. Family history and social history were nonsignificant.
Prenatal cfDNA screening previously performed was low risk for trisomies 21, 18, and 13, monosomy X, and 22q11.2 deletion syndrome. Carrier screening for 27 autosomal recessive and X-linked conditions was also low risk.
Diagnostic Workup
Detailed ultrasound demonstrated severe bilateral ventriculomegaly, macrocephaly, absent corpus callosum (CC), absent cavum septum pellucidum (CSP), a dilated 3rd ventricle, and a small cerebellum. The remaining anatomic survey appeared normal. A fetal MRI was ordered and showed an incomplete CSP anteriorly. It was otherwise consistent with ultrasound findings. Fetal echocardiogram was normal.
The patient was referred to genetic counseling and elected for an amniocentesis at 21 weeks’ gestation. FISH was normal for chromosomes 13, 18, 21, X and Y. Karyotype was normal: 46,XY. Amniotic fluid PCR for cytomegalovirus, parvovirus and toxoplasmosis returned negative, and amniotic fluid AFP was normal. Chromosomal microarray analysis (CMA) revealed a 1.73 MB distal duplication of 1q21.1>q21.2: arr[hg19] 1q21.1q21.2(146,105,171-147,830,903) x3. This region includes 10 OMIM genes (NBPF14, PRKAB2, CHD1L, FMO5, BCL9, ACP6, GJA5, GJA8, GPR89B, NBPF11). Exome sequencing was negative except for the duplication noted on CMA.
Treatment and Management
The patient was counseled on all management options and elected for continuation of pregnancy. She was subsequently diagnosed with gestational diabetes and anemia requiring Metformin and IV iron infusions. She underwent neonatology and pediatric neurosurgery consultations antenatally. Serial growth ultrasounds and antenatal testing were performed revealing polyhydramnios at 28 weeks and large for gestational age (LGA) fetus at 31 weeks that persisted. Head circumference and biparietal diameter measured greater than the 95th percentile.
Outcome and Follow-Up
The patient underwent an uncomplicated Cesarean section at 36 weeks for decreased fetal movement, preterm labor, and breech presentation. A male infant was delivered with birth weight 4340 grams and APGARS 2, 6, and 7 at 1, 5, and 10 minutes, respectively. Postnatal findings included macrocephaly with frontal bossing, a mildly dilated ascending aorta, an anorectal malformation, and disordered eye movements. Imaging confirmed marked hydrocephalus with CC hypoplasia, absence of the CSP, and an arachnoid cyst. The infant underwent subgaleal shunt placement and diverting colostomy on day 2 of life, third ventriculostomy at 1 week of life, ventriculoperitoneal shunt placement at 2 weeks, and anorectoplasty at 5 months. He has developmental delays and is enrolled in Early Intervention.
Discussion
To our knowledge, this is the first case reporting absent CSP and anorectal malformation in an individual with 1q21.1 duplication. Additionally, while previous cases reported fetal ventriculomegaly, none were reported to be as severe as noted here. This case highlights the high phenotypic variability of 1q21.1 duplication and resulting challenges posed in genetic counseling in the prenatal setting.
Conclusion
Further studies are needed to determine the function of the genes implicated in this duplication and the molecular mechanisms underlying these novel findings.
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