Next-Generation Sequencing Gene Panels and “Solo” Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses

Abstract

<b><i>Objective:</i></b> The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. <b><i>Methodology:</i></b> Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. <b><i>Results:</i></b> During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. <b><i>Conclusions:</i></b> A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta‐analysis

“…In relation to the diagnostic yield of individual anatomical systems involved in cases with multisystem anomalies, the highest yields were observed for craniofacial dysmorphism (47% of fetuses with this anomaly were positive on ES), central nervous system anomalies (45%) and musculoskeletal anomalies (43%), while the lowest yields were for fetal hydrops (19%) and gastrointestinal anomalies (27%) (Figure 4 and Table S1). Among the 17 selected studies, only three reported data on incidental findings 22,31,32 , resulting in a frequency ranging from 1.1% to 6.1%, while four reported on secondary findings 4,26,27,29 , with a frequency ranging from 3.9% to 21%.…”

“…Among the 121 abstracts found at that search, 24 articles were reviewed fully, of which 16 were deemed eligible for inclusion in the study 4,5,[18][19][20][21][22][23][24][25][26][27][28][29][30][31] . Finally, our own series 32 was added. Among the 17 studies included in this systematic review, there were seven in which whole ES was performed, eight series in which only the OMIM genes were studied and two series in which the interpretation approach was not specified.…”

“…Regarding the description of structural anomalies in individual fetuses, this was lacking in two studies 4,30 , while in three studies it was provided only for positive cases 5,22,31 . Among the remaining 12 studies [18][19][20][21][23][24][25][26][27][28][29]32 , the mean number of systems involved was 2.8 (1079/383) per fetus (Table S1). The highest proportion of anomalies was observed for the musculoskeletal system (19%) and the central nervous system (18%), while the lowest proportions were observed among respiratory anomalies (3%) and fetal hydrops (3%) (Table S1).…”

“…Among the 213 cases with a positive molecular diagnosis on ES, 223 genes were found to be involved, with more than one gene being involved in 10 positive cases. The genes most frequently affected were the following: the KMT2D gene, associated with Kabuki syndrome (n = 11), the CHD7 gene, related to CHARGE syndrome (n = 7), the FGFR2-related Study Carss (2014) 18 Alamillo (2015) 19 Yates (2017) 20 Normand (2018) 21 Fu (2018) 22 Aarabi (2018) 23 Meier (2019) 24 Lord (2019) 4 Petrovski (2019) 5 Daum (2019) 25 De Koning (2019) 26 Corsten-Janssen (2020) 27 Deden (2020) 28 Vora (2020) 29 Becher (2020) 30 Diderich (2021) 31 Pauta (2021) 32 disorders gene (n = 5) and the DHCR7 gene, related to Smith-Lemli-Opitz syndrome (n = 5). A gene involved in the group of RASopathy syndromes was found in 22 positive cases, specifically the following genes: PTPN11 (n = 5), RIT1 (n = 4), HRAS (n = 4), KRAS (n = 2), SOS1 (n = 2), RAF1 (n = 2), BRAF (n = 2) and NRAS (n = 1).…”

Postnatal genetic and neurodevelopmental assessment in infants born at term with severely low birth weight of non‐placental origin

“…DNA quality was determined by optical density using a DeNovix DS-11 instrument (Wilmington, DE, USA). The human exome was enriched using the KAPA HyperExome assay (Roche NimbleGen, Pleasanton, CA, USA) and massively sequenced using NovaSeq 6000 equipment (Illumina, San Diego, CA, USA), as described previously 12 . The average coverage depth achieved along the target regions was 65-140 × .…”