Additional haplotype in NIPD for Spinal muscular atrophy: triploid of a twin gestation
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Relative haplotype dosage change analysis is the main steam for Spinal muscular atrophy (SMA) noninvasive prenatal diagnosis. For singleton pregnancy, there two maternal haplotypes and one paternal haplotype in the maternal circulation. In this SMA singleton pregnancy, we observed two paternal haplotypes in the plasma.
Case Presentation
This is a 27-year-old, 8W4D pregnant woman ,carrying with SMN1 gene Exon7-8 deletion. The father carried the same deletion. Ultrasound scan in the early pregnancy confirms a live single pregnancy. During the NIPD RHDO analysis, an additional paternal haplotypes were observed in the maternal plasma.
Diagnostic Workup
The following four hypotheses are proposed to account for the additional paternal haplotype. (1) The fetus was trisomy 5. (2) The fetus was diandric triploid. Triploid often leads to abortion in the first trimester. (3) The fetus is unrecognized ongoing twin pregnancy or a vanishing twin. Follow-up ultrasound testing is required for validation. (4) confined placental mosaicism (CPM).
Treatment and Management
The dosage change (DC) of additional and expected paternal haplotype were both nearly to ff/4. And the inherited maternal DC was nearly to ff/2
Firstly, we supposed this is a singleton pregnancy.
If the fetuses were Trisomy 5, the DC of paternal haplotype Hap1 and Hap2 should be both ff/2. However, sequencing data indicated that the DC for paternal haplotype is nearly close to ff/4, which did not support the hypothesis of trisomy 5.
If the fetuses were triploid, the DC of paternal haplotype Hap1 and Hap2 should be both ff/4, as the same as this case. The fetus was probably a diandric triploid.
If CPM lead to additional haplotype, it is impossible the placent haplotype had the same DC as the fetal haplotype. It did not support CPM.
Secondly, we supposed this is a twin pregnancy.
If the dizygotic twins inherited the same maternal haplotype and different paternal haplotype, the two fetal fraction were probably different. However, the twin individual fetal fraction were same, which did not support the hypothesis of DZ twin.
Outcome and Follow-Up
We infer that the possibility of trisomy is the highest.
At 11 gestational weeks, miscarriage happened in this case. There are two gestational sacs in the products of conception. After the STR testing, the two fetuses were diagnosed as the monozygotic diandric triploid twin. We performed MPLA to validate the fetal genotype, twins inherited the maternal normal SMN gene and paternal normal SMN genes.
Discussion
For unexpected founding, haplotype-based NIPD can observe unexpected twin pregnancy and triploid. For twin pregnancy, this algorithm could also predict the combination of fetal haplotypes. And for fetal triploid, NIPT could indicate an unexpected dosage change of haplotype. With the help of ultrasound and invasive procedures, the majority of these cases could be revealed.
Conclusion
Haplotype-based noninvasive prenatal diagnosis can have unexpected founding and interprets different cases through dosage change. This case may provide an insight into appropriate clinical care in these patients and a wider field for relative haplotype dosage analysis
Relative haplotype dosage change analysis is the main steam for Spinal muscular atrophy (SMA) noninvasive prenatal diagnosis. For singleton pregnancy, there two maternal haplotypes and one paternal haplotype in the maternal circulation. In this SMA singleton pregnancy, we observed two paternal haplotypes in the plasma.
Case Presentation
This is a 27-year-old, 8W4D pregnant woman ,carrying with SMN1 gene Exon7-8 deletion. The father carried the same deletion. Ultrasound scan in the early pregnancy confirms a live single pregnancy. During the NIPD RHDO analysis, an additional paternal haplotypes were observed in the maternal plasma.
Diagnostic Workup
The following four hypotheses are proposed to account for the additional paternal haplotype. (1) The fetus was trisomy 5. (2) The fetus was diandric triploid. Triploid often leads to abortion in the first trimester. (3) The fetus is unrecognized ongoing twin pregnancy or a vanishing twin. Follow-up ultrasound testing is required for validation. (4) confined placental mosaicism (CPM).
Treatment and Management
The dosage change (DC) of additional and expected paternal haplotype were both nearly to ff/4. And the inherited maternal DC was nearly to ff/2
Firstly, we supposed this is a singleton pregnancy.
If the fetuses were Trisomy 5, the DC of paternal haplotype Hap1 and Hap2 should be both ff/2. However, sequencing data indicated that the DC for paternal haplotype is nearly close to ff/4, which did not support the hypothesis of trisomy 5.
If the fetuses were triploid, the DC of paternal haplotype Hap1 and Hap2 should be both ff/4, as the same as this case. The fetus was probably a diandric triploid.
If CPM lead to additional haplotype, it is impossible the placent haplotype had the same DC as the fetal haplotype. It did not support CPM.
Secondly, we supposed this is a twin pregnancy.
If the dizygotic twins inherited the same maternal haplotype and different paternal haplotype, the two fetal fraction were probably different. However, the twin individual fetal fraction were same, which did not support the hypothesis of DZ twin.
Outcome and Follow-Up
We infer that the possibility of trisomy is the highest.
At 11 gestational weeks, miscarriage happened in this case. There are two gestational sacs in the products of conception. After the STR testing, the two fetuses were diagnosed as the monozygotic diandric triploid twin. We performed MPLA to validate the fetal genotype, twins inherited the maternal normal SMN gene and paternal normal SMN genes.
Discussion
For unexpected founding, haplotype-based NIPD can observe unexpected twin pregnancy and triploid. For twin pregnancy, this algorithm could also predict the combination of fetal haplotypes. And for fetal triploid, NIPT could indicate an unexpected dosage change of haplotype. With the help of ultrasound and invasive procedures, the majority of these cases could be revealed.
Conclusion
Haplotype-based noninvasive prenatal diagnosis can have unexpected founding and interprets different cases through dosage change. This case may provide an insight into appropriate clinical care in these patients and a wider field for relative haplotype dosage analysis
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