Medical Genetic Diagnosis and Therapy Center, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, 350001, Fuzhou, China.
Fujian Obstetrics and Gynecology Hospital, Fuzhou, 350011, Fujian, China.
J Hum Genet. 2022 Nov;67(11):629-638. doi: 10.1038/s10038-022-01062-9. Epub 2022 Jul 27.
Region of homozygosity (ROH) is classified as uniparental disomy (UPD) or identity by descent, depending on its origin. To explore the clinical relevance of ROH in prenatal diagnoses, we reviewed 5063 fetal samples subjected to single nucleotide polymorphism array at our center over 5 years. ROH cases meeting our reporting threshold were further analyzed. ROHs were detected in 22 fetuses (0.43%, 22/5063), of which, 77.3% (17/22) showed a ROH on a single chromosome and 22.7% (5/22) showed multiple ROHs on different chromosomes. Among 5063 fetuses undergoing invasive prenatal diagnoses owing to various indications, five cases were identified as UPDs with a rate of ~1/1000. We observed clinically relevant UPDs in two cases related to Prader-Willi syndrome and transient neonatal diabetes mellitus. Of note, one case showed 50% mosaicism for trisomy 2 in amniotic fluid, whereas a complete UPD (2) was observed in umbilical cord blood. Trio whole-exome sequencing was performed for three cases. Clinically relevant variants were identified in two cases, one of which, NM_000302:c.2071_2072insCC (p.R693Qfs*122) in PLOD1 located in the ROH, may be related to Ehlers-Danlos syndrome, kyphoscoliotic type, 1. Overall, 72.7% (16/22) of the ROH carriers showed ultrasound abnormalities, of whom eight (50%, 8/16) had adverse perinatal outcomes. Our study demonstrates that the clinical relevance of ROHs should be examined regarding fetuses with ROHs occurring on imprinted chromosomes or those derived from consanguineous parents in prenatal diagnoses; imprinting disorders and/or autosomal recessive diseases attributed to ROHs should be considered during genetic counseling.
同源区域（ROH）根据其来源分为单亲二体（UPD）或同源一致。为了探讨产前诊断中 ROH 的临床相关性，我们回顾了 5 年来在本中心进行单核苷酸多态性微阵列分析的 5063 例胎儿样本。符合我们报告标准的 ROH 病例进一步进行了分析。在 22 例胎儿中检测到 ROH（0.43%，22/5063），其中 77.3%（17/22）显示单个染色体上的 ROH，22.7%（5/22）显示不同染色体上的多个 ROH。在因各种原因进行侵袭性产前诊断的 5063 例胎儿中，有 5 例被确定为 UPD，发生率约为 1/1000。我们观察到与普拉德-威利综合征和短暂性新生儿糖尿病相关的两个具有临床相关性的 UPD。值得注意的是，一例羊水存在 2 号染色体三体 50%镶嵌现象，而脐带血中观察到完全 UPD（2）。对 3 例进行了三体外显子组测序。在 2 例中鉴定出具有临床相关性的变异，其中一例 PLOD1 基因中的 NM_000302:c.2071_2072insCC（p.R693Qfs*122）错义变异可能与埃勒斯-当洛斯综合征、脊柱后侧凸型、1 型相关。总体而言，22 例 ROH 携带者中 72.7%（16/22）有超声异常，其中 8 例（50%，8/16）有不良围产期结局。我们的研究表明，在产前诊断中，对于发生在印迹染色体上的 ROH 胎儿或源自近亲父母的 ROH 胎儿，应检查 ROH 的临床相关性；在遗传咨询中应考虑到 ROH 引起的印迹障碍和/或常染色体隐性疾病。
