講演情報
[OE8-4]Current approaches on Harlequin ichthyosis from early prenatal diagnosis to prevention by advanced reproductive technology - two case series
○Wu Wan-Ju1,2,3, Tzu Chu-Yi3, Ma Gwo-Chin1,2, Chang Ting-Yu1,2, Chen Ming1,2,3 (1.Department of Genomic Medicine and Center for Medical Genetics, Changhua Christian Hospital, Changhua, Taiwan., 2.Department of Genomic Science and Technology, Changhua Christian Hospital Healthcare System, Changhua, Taiwan, 3.Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan)
Background: Harlequin ichthyosis (HI, OMIM #242500) is an extremely rare and severe subtype of autosomal recessive congenital ichthyosis (ARCI). The affected individuals are characterized by thicken and plate-like scales of skin covering the entire body surface. ABCA12 gene is known as the genetic cause by affecting lipid transportation to epidermis and devastating normal skin barrier. With the advance of prenatal diagnostic facilities, it is feasible to diagnose HI in utero and even offer proper preventive statics by the way of artificial reproductive technology in combination with preimplantation genetic tests.<br/>
Methods: We presented two series of HI that were diagnosed by prenatal sonographic features and confirmed by postmortem whole exon sequencing (WES). When we further implemented the genetic findings in their next pregnancies, various methodologies from in-house amplification refractory mutation system quantitative polymerase chain reaction (ARMS-qPCR), linkage analysis and Sanger sequencing were employed according to different clinical scenarios.<br/>
Results: In family 1, the WES only revealed a heterozygous mutation c.6858delT (p.F2286fs) on ABCA12 gene. We therefore employed a combination of mutation detection with analysis of nearby linked STR makers to identify the affected offspring in their following prenatal settings, including one natural pregnancy without the presence of typical phenotypes. The women finally delivered two healthy babies by the way of PGT with ARMS-qPCR in combination with linkage analysis. In family 2, the trio-WES yielded two likely pathological variants with compound heterozygous inheritance at ABCA12 gene, chr2 g.214948694A>G:NM_015657.3:c.6052T>C:p.C2018R of maternal inheritance and chr2 g.214937608G>A:NM_015657.3:c.6490C>T:p.R2164* of paternal inheritance. They underwent two failed courses of IVF +PGT-M by standard ARMS-qPCR. The couple now conceive naturally and amniocentesis with Sanger sequencing analysis will be conducted to detect the affected offspring. <br/>
Conclusions: Given the presence of advancing ultrasound equipments and genetic platforms, HI would not be an unpredictable and inescapable disease. Despite current sophisticated sequencing tools facilitate the diagnosis of certain rare diseases, there remains a potential for failure to detect a pathological variant. To fulfill the requirement of prenatal tests and PGT-M, physicians should integrate different methods to identify affected offspring when either or both biological contributor are known carriers.
Methods: We presented two series of HI that were diagnosed by prenatal sonographic features and confirmed by postmortem whole exon sequencing (WES). When we further implemented the genetic findings in their next pregnancies, various methodologies from in-house amplification refractory mutation system quantitative polymerase chain reaction (ARMS-qPCR), linkage analysis and Sanger sequencing were employed according to different clinical scenarios.<br/>
Results: In family 1, the WES only revealed a heterozygous mutation c.6858delT (p.F2286fs) on ABCA12 gene. We therefore employed a combination of mutation detection with analysis of nearby linked STR makers to identify the affected offspring in their following prenatal settings, including one natural pregnancy without the presence of typical phenotypes. The women finally delivered two healthy babies by the way of PGT with ARMS-qPCR in combination with linkage analysis. In family 2, the trio-WES yielded two likely pathological variants with compound heterozygous inheritance at ABCA12 gene, chr2 g.214948694A>G:NM_015657.3:c.6052T>C:p.C2018R of maternal inheritance and chr2 g.214937608G>A:NM_015657.3:c.6490C>T:p.R2164* of paternal inheritance. They underwent two failed courses of IVF +PGT-M by standard ARMS-qPCR. The couple now conceive naturally and amniocentesis with Sanger sequencing analysis will be conducted to detect the affected offspring. <br/>
Conclusions: Given the presence of advancing ultrasound equipments and genetic platforms, HI would not be an unpredictable and inescapable disease. Despite current sophisticated sequencing tools facilitate the diagnosis of certain rare diseases, there remains a potential for failure to detect a pathological variant. To fulfill the requirement of prenatal tests and PGT-M, physicians should integrate different methods to identify affected offspring when either or both biological contributor are known carriers.