Genomic Study of Severe Fetal Anomalies and Discovery of GREB1L Mutations in Renal Agenesis

Boissel, Sarah; Fallet-Bianco, Catherine; Chitayat, David; Kremer, Valérie; Nassif, Christina; Rypens, Françoise; Delrue, Marie‐Ange; Soglio, Dorothée Dal; Oligny, Luc L.; Patey, Natalie; Flori, Elisabeth; Cloutier, Michel; Dyment, David A.; Campeau, Philippe M.; Karalis, Aspasia; Nizard, Sonia; Fraser, William D.; Audibert, François; Lemyre, Emmanuelle; Rouleau, Guy A.; Hamdan, Fadi F.; Kibar, Zoha; Michaud, Jacques L.

doi:10.1097/01.ogx.0000550387.91867.88

Cited by 7 publications

(13 citation statements)

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“…To date, 28 pathogenic variants in FAM20C have been reported in association with Raine syndrome of which 19/28 are missense variants (Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood N., 2014; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ) (Table S1). These 19 reported pathogenic missense variants and polymorphisms identified in nominally healthy reference population were mapped onto the 3D structure of the FAM20C protein (Berman et al, ; Lek et al, ) (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…To date, 28 different mutations in FAM20C have been reported in association with Raine syndrome, including missense variants ( n = 19), nonsense variants ( n = 1), splice site variants ( n = 5), and complex rearrangements ( n = 3) (Ababneh et al, ; Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood, Donne, Weber, & Dharmaraj, ; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ). The genotype–phenotype correlation is unknown.…”

Section: Introductionmentioning

confidence: 99%

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A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

Hung

Rodrı́guez

Roberts

et al. 2019

American J of Med Genetics Pt A

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Raine syndrome is a rare, autosomal recessive, osteosclerotic bone dysplasia due to pathogenic variants in FAM20C. The clinical phenotype is characterized by generalized osteosclerosis affecting all bones, cerebral calcifications, and craniofacial dysmorphism.Most cases present during the neonatal period with early lethality due to pulmonary hypoplasia and respiratory compromise while only few affected individuals have been reported to survive into adulthood. FAM20C is a ubiquitously expressed protein kinase that contains five functional domains including a catalytic domain, a binding pocket for FAM20A and three distinct N-glycosylation sites. We report a newborn infant with a history of prenatal onset fractures, generalized osteosclerosis, and craniofacial dysmorphism and early lethality. The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p. Met336Arg) was identified by targeted Sanger sequencing. Following in silico analysis and mapping of the variant on a three-dimensional (3D) model of FAM20C it is predicted to be deleterious and to affect N-glycosylation, protein folding, and subsequent secretion of FAM20C. In addition, we reviewed all published FAM20C mutations and observed that most pathogenic variants affect functional regions within the protein establishing evidence for an emerging genotype-phenotype correlation. K E Y W O R D S FAM20C, osteosclerosis, Raine syndrome

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

Hung

Rodrı́guez

Roberts

et al. 2019

American J of Med Genetics Pt A

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“…Group A: A total of 17 papers were included [13,75,[200][201][202][203][204][205][206][207][208][209][210][211][212][213][214] (Table S3). Group B: A total of 27 cohorts were enrolled [98,196, (Table S4).…”

Section: Exome Sequencingmentioning

confidence: 99%

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

et al. 2022

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Fetal malformations occur in 2–3% of pregnancies. They require invasive procedures for cytogenetics and molecular testing. “Structural anomalies” include non-transient anatomic alterations. “Soft markers” are often transient minor ultrasound findings. Anomalies not fitting these definitions are categorized as “dynamic”. This meta-analysis aims to evaluate the diagnostic yield and the rates of variants of uncertain significance (VUSs) in fetuses undergoing molecular testing (chromosomal microarray (CMA), exome sequencing (ES), genome sequencing (WGS)) due to ultrasound findings. The CMA diagnostic yield was 2.15% in single soft markers (vs. 0.79% baseline risk), 3.44% in multiple soft markers, 3.66% in single structural anomalies and 8.57% in multiple structural anomalies. Rates for specific subcategories vary significantly. ES showed a diagnostic rate of 19.47%, reaching 27.47% in multiple structural anomalies. WGS data did not allow meta-analysis. In fetal structural anomalies, CMA is a first-tier test, but should be integrated with karyotype and parental segregations. In this class of fetuses, ES presents a very high incremental yield, with a significant VUSs burden, so we encourage its use in selected cases. Soft markers present heterogeneous CMA results from each other, some of them with risks comparable to structural anomalies, and would benefit from molecular analysis. The diagnostic rate of multiple soft markers poses a solid indication to CMA.

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“…For the study of Petrovski et al 16 , based in Columbia University Medical Centre, New York, USA, the authors provided an extended dataset. In total, in addition to the extended PAGE study cohort, a further 20 studies met the inclusion criteria (Figure 1) 2,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] . Table 1 shows the characteristics of the included studies and Figure 2 shows the overall quality assessment.…”

Section: Systematic Review and Meta-analysismentioning

confidence: 99%

“…Becher (2020) 26 Boissel (2018) 18 Corsten-Janssen (2020) 32 Croonen (2013) 33 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 Normand (2018) 21 Petrovski (2019) 16 Sparks (2019) 29 Sparks (2020) 2 Stals (2018) 23 Vora (2017) 22 Westerfield (2015) 30 Westphal (2019) 24 Yang (2012) 31 Yates (2017) 25 Zhou (2020) 17 17 Study or subgroup Becher (2020) 26 Corsten-Janssen (2020) 32 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 1.8% 6.3% 23 Westerfield (2015) 30 Westphal (2019) 24 Zhou (2020) 17 Corsten-Janssen (2020) 32 Study or subgroup Boissel (2018) 18 Deden (2020) 27 Deng (2020) 19 Greenbaum (2019) 28 Jelin (2020) 20 Lord (2019) 8 Mone (2020) 34 Petrovski (2019) 16 Sparks (2020) The findings of the extended PAGE cohort and the systematic review were broadly concordant, but with a lower incremental yield of ES in the cohort study, which may be explained by the smaller number of cases as well as the unselected approach to case selection. The high incidence of RASopathies and of de-novo varian...…”

Section: Study or Subgroupmentioning

confidence: 99%

Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis

Mone

Eberhardt

Hurles

et al. 2021

Ultrasound in Obstet & Gyne

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Objective To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non‐immune hydrops fetalis (NIHF). Methods A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and http://ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound‐based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). Results In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non‐isolated NIHF. In the meta‐analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24–34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13–30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30–49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). Conclusions Use of prenatal next‐generation sequencing in both isolated and non‐isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole‐genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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Genomic Study of Severe Fetal Anomalies and Discovery of GREB1L Mutations in Renal Agenesis

Cited by 7 publications

References 0 publications

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

Fetal hydrops and the Incremental yield of Next‐generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta‐analysis

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