Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations

Abstract

Background: The potential correlations between chromosomal abnormalities and craniofacial malformations (CFMs) remain a challenge in prenatal diagnosis. This study aimed to evaluate 118 fetuses with CFMs by applying chromosomal microarray analysis (CMA) and G-banded chromosome analysis. Results: Of the 118 cases in this study, 39.8% were isolated CFMs (47/118) whereas 60.2% were non-isolated CFMs (71/118). The detection rate of chromosomal abnormalities in non-isolated CFM fetuses was significantly higher than that in isolated CFM fetuses (26/71 vs. 7/47, p = 0.01). Compared to the 16 fetuses (16/104; 15.4%) with pathogenic chromosomal abnormalities detected by karyotype analysis, CMA identified a total of 33 fetuses (33/118; 28.0%) with clinically significant findings. These 33 fetuses included cases with aneuploidy abnormalities (14/118; 11.9%), microdeletion/microduplication syndromes (9/118; 7.6%), and other pathogenic copy number variations (CNVs) only (10/118; 8.5%).We further explored the CNV/phenotype correlation and found a series of clear or suspected dosage-sensitive CFM genes including TBX1, MAPK1, PCYT1A, DLG1, LHX1, SHH, SF3B4, FOXC1, ZIC2, CREBBP, SNRPB, and CSNK2A1. Conclusion: These findings enrich our understanding of the potential causative CNVs and genes in CFMs. Identification of the genetic basis of CFMs contributes to our understanding of their pathogenesis and allows detailed genetic counselling.

The genetic landscape of copy number variation in a Vietnamese cohort of 5008 fetuses with clinical anomalies during pregnancy

“…Overall, 3,393 (67.75%) fetuses were identi ed to have structural anomalies in at least one system. Our study revealed that the prevalence of abnormal CNVs from congenital structural anomalies in the cardiovascular system (18.91%), skeletomuscular system (10.48%), central nervous system (11.11%), craniofacial structures (11.59%), urogenital system (18.48%), and digestive system (15.69%) were consistent with previously reported data from other populations (Table 3) [29][30][31][32][33][34][35] . Next, we investigated the association between abnormal CNVs and multiple types of structural anomalies.…”

“…Many ultrasound soft markers such as echogenic intracardiac focus, echogenic bowel, fetal ventriculomegaly, hypoplastic/aplastic nasal bone, and nuchal translucency have been investigated for their relationships with abnormal CNVs [17][18][19][20][21][22][23][24][25] . Multiple congenital structural anomalies have been studied for their correlations with CNVs in early prenatal diagnosis [26][27][28][29][30][31][32][33][34][35][36][37] . In addition, CNV has also shown its applicability among fetuses with sonographic abnormalities but normal karyotypes from traditional diagnostic methods in late pregnancy 38 .…”

Prenatal Diagnosis and Pregnancy Outcomes of Fetuses With Orofacial Cleft: A Retrospective Cohort Study in Two Centres in Hong Kong

“…Similarly, Jin et al 17 have reported an increased detection rate of approximately 4%. Xu et al 18 have also shown a 12.6% additional detection rate in a Chinese retrospective cohort. Our study has demonstrated an incremental diagnostic yield of 6.1% (4/66) by CMA (16.7%) over karyotyping (10.6%) compatible with other studies, which supported the policy change for the universal application of CMA for invasive prenatal testing in Hong Kong.…”

Inherited loss of function variant in CSNK2A1: the oldest reported cases of Okur–Chung syndrome in a single family

“…MRI often reveals cortical neuronal migration defects. Published variants to date include 27 missense, 1 loss of start codon leading to loss of the first 137 amino acids in N terminal, 2 nonsense variants, 1 frameshift variant and 2 splice site variants (Okur et al ., 2016; Trinh et al ., 2017; Akahira-Azuma et al ., 2018; Chiu et al ., 2018; Colavito et al ., 2018; Owen et al ., 2018; Duan et al ., 2019; Nakashima et al ., 2019; Martinez-Monseny et al ., 2020; Wu et al ., 2020, 2021; Xu et al ., 2020a, b; Ranganath et al ., 2021; Jafari Khamirani et al ., 2022; Murakami et al ., 2022; Belnap et al ., 2023; Drenushe et al ., 2024; Wafik et al ., 2023). Clinvar and DECIPHER, however, list 25 and 3 loss of function variants, respectively including nonsense, frameshift and splice site variants.…”