Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions

Burgess, Trent; Brown, Natasha J; Stark, Zornitza; Bruno, Damien L.; Oertel, Ralph; Chong, Belinda; Calabro, Vanessa; Kornberg, Andrew J.; Sanderson, Christine; Kelly, Janice M.; Howell, Katherine; Savarirayan, Ravi; Hinds, Rupert; Greenway, Anthea; Slater, Howard R.; White, Susan

doi:10.1002/ajmg.a.36203

Cited by 17 publications

(18 citation statements)

References 20 publications

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“…Due to incomplete penetrance and a variable phenotype, these CNVs also raised concerns and frustration among parents, which lead to confusion regarding the future health and development of the offspring. In the present study, among seven cases (Cases 2, 4-8, 10) [13][14][15][16][17][18][19], six were de novo, while one was maternally inherited; in four cases (Cases 1, 3, 9, 11) [20][21][22][23], the parents were not tested; however, from three of the (Cases 1, 3, 11) cases, one was observed with an abnormality in the ultrasound, in addition to the NT. Nevertheless, the clinical significance of these variants cannot be predicted before parental confirmation.…”

Section: Discussioncontrasting

confidence: 43%

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

Lee¹,

Go²,

Na³

et al. 2020

J Genet Med

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Purpose: To evaluate the additive value of prenatal chromosomal microarray analysis (CMA) in assessing increased nuchal translucency (NT) (≥3.5 mm) with normal karyotype and the possibility of detecting clinically significant genomic imbalance, based on specific indications. Materials and Methods: Invasive samples from 494 pregnancies with NT ≥3.5 mm, obtained from the Research Center of Fertility & Genetics of Hamchoon Women's Clinic between January 2019 and February 2020, were included in this study and CMA was performed in addition to a standard karyotype. Results: In total, 494 cases were subjected to both karyotype and CMA analyses. Among these, 199 cases of aneuploidy were excluded. CMA was performed on the remaining 295 cases (59.7%), which showed normal (231/295, 78.3%) or non-significant copy number variation (CNV), such as benign CNV or variants of uncertain clinical significance likely benign (53/295, 18.0%). Clinically significant CNVs were detected in 11 cases (11/295, 3.7%). Conclusion: Prenatal CMA resulted in a 3% to 4% higher CNV diagnosis rate in fetuses exhibiting increased NT (≥3.5 mm) without other ultrasound detected anomalies and normal karyotype. Therefore, we suggest using high resolution, non-targeting CMA to provide valuable additional information for prenatal diagnosis. Further, we recommend that a genetics specialist should be consulted to interpret the information appropriately and provide counseling and follow-up services after prenatal CMA.

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Section: Discussioncontrasting

confidence: 43%

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

Lee¹,

Go²,

Na³

et al. 2020

J Genet Med

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“…In previous studies, recurrent deletions of 15q25.2 (on which, the RPS17 gene is located) have been associated with increased risk of CDH and cognitive deficits, with or without other features of DBA. [10,11] However, there is no recorded case of both Bochdalek hernia and DBA having occurred simultaneously. Although McFarren et al have reported the case of DBA patient with CDH associated with mutations of RPS19 and RPS24 genes, the hernia was of a right-sided Morgagni type.…”

Section: Discussionmentioning

confidence: 99%

Bochdalek hernia with Diamond-Blackfan anemia associated with RPS19 gene mutation

2019

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Rationale:Diamond-Blackfan anemia (DBA) is a rare inherited marrow disorder, characterized by erythrocyte aplasia and is associated with congenital anomalies and a susceptibility to cancer. Although congenital abnormalities have been observed in ∼50% of DBA patients, the occurrence of an associated congenital diaphragmatic hernia (CDH) has rarely been reported.Patient concerns:A 19-month-old male child was referred to our pediatric hematology-oncology outpatient clinic with anemic appearance. He presented to us with recurrent anemia, short stature, and developmental delay.Diagnosis:On bone marrow examination, only erythropoietic cells were markedly decreased in number, whereas other cell lines were unaffected. An abdominal computed tomography scan revealed a Bochdalek type of CDH. A genetic analysis revealed heterozygous mutation of RPS19; therefore, he was diagnosed as having DBA with CDH.Interventions:The patient received an initial packed red blood cell transfusion, followed by an administration of oral prednisone.Outcomes:The patient is maintained on oral prednisone administered at a dose of 0.3 mg/kg every alternate day and has since a hemoglobin level of >9.0 g/dL without further RBC transfusions.Lessons:We learned that a Bochdalek type of CDH can manifest in a DBA patient with RPS19 gene mutation. Therefore, patients diagnosed with the latter disorder should also be screened for an early detection of potential CDHs.

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“…The WHAMM and WDR73 genes are separated by only 1.7 Mb, and several humans with chromosome 15 microdeletions encompassing WHAMM or both WHAMM and WDR73 exhibit developmental delay or intellectual disability ( Doelken et al. , 2013 ; Burgess et al. , 2014 ).…”

Section: Discussionmentioning

confidence: 99%

An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex–driven autophagosomal remodeling pathway

Mathiowetz

Baple

Russo

et al. 2017

MBoC

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Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions

Cited by 17 publications

References 20 publications

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

Bochdalek hernia with Diamond-Blackfan anemia associated with RPS19 gene mutation

An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex–driven autophagosomal remodeling pathway

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