Application of Whole Exome Sequencing in Diagnosis of Pediatric Acute Liver Failure of Unknown Etiology

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

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Molecular defects identified by whole exome sequencing in a child with atypical mucopolysaccharidosis IIIB

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2016-0333 ◽

2017 ◽

Vol 30 (4) ◽

Cited By ~ 6

Author(s):

Qingwen Zeng ◽

Yanjie Fan ◽

Lili Wang ◽

Zhuo Huang ◽

Xuefan Gu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Unknown Etiology ◽

Mendelian Disease ◽

Atypical Form ◽

Pathogenic Variants ◽

Diagnostic Potential ◽

Whole Exome ◽

Related Enzyme

AbstractBackground:Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in theCase presentation:Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient’s blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in theConclusions:Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

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Digenic Variants in the FGF21 Signaling Pathway Associated with Severe Insulin Resistance and Pseudoacromegaly

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa138 ◽

2020 ◽

Vol 4 (12) ◽

Author(s):

Stephen I Stone ◽

Daniel J Wegner ◽

Jennifer A Wambach ◽

F Sessions Cole ◽

Fumihiko Urano ◽

...

Keyword(s):

Insulin Resistance ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Unknown Etiology ◽

Fibroblast Growth Factor 21 ◽

Severe Insulin Resistance ◽

Whole Exome

Abstract Insulin-mediated pseudoacromegaly (IMPA) is a rare disease of unknown etiology. Here we report a 12-year-old female with acanthosis nigricans, hirsutism, and acromegalic features characteristic of IMPA. The subject was noted to have normal growth hormone secretion, with extremely elevated insulin levels. Studies were undertaken to determine a potential genetic etiology for IMPA. The proband and her family members underwent whole exome sequencing. Functional studies were undertaken to validate the pathogenicity of candidate variant alleles. Whole exome sequencing identified monoallelic, predicted deleterious variants in genes that mediate fibroblast growth factor 21 (FGF21) signaling, FGFR1 and KLB, which were inherited in trans from each parent. FGF21 has multiple metabolic functions but no known role in human insulin resistance syndromes. Analysis of the function of the FGFR1 and KLB variants in vitro showed greatly attenuated ERK phosphorylation in response to FGF21, but not FGF2, suggesting that these variants act synergistically to inhibit endocrine FGF21 signaling but not canonical FGF2 signaling. Therefore, digenic variants in FGFR1 and KLB provide a potential explanation for the subject’s severe insulin resistance and may represent a novel category of insulin resistance syndromes related to FGF21.

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Utility of rapid whole-exome sequencing in the diagnosis of Niemann–Pick disease type C presenting with fetal hydrops and acute liver failure

Molecular Case Studies ◽

10.1101/mcs.a002147 ◽

2017 ◽

Vol 3 (6) ◽

pp. a002147 ◽

Cited By ~ 6

Author(s):

Mersedeh Rohanizadegan ◽

Sara M. Abdo ◽

Anne O'Donnell-Luria ◽

Ivana Mihalek ◽

Peggy Chen ◽

...

Keyword(s):

Liver Failure ◽

Acute Liver Failure ◽

Exome Sequencing ◽

Disease Type ◽

Fetal Hydrops ◽

Niemann Pick Disease ◽

Whole Exome ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Using whole‐exome sequencing to investigate the genetic bases of lysosomal storage diseases of unknown etiology

Human Mutation ◽

10.1002/humu.23291 ◽

2017 ◽

Vol 38 (11) ◽

pp. 1491-1499 ◽

Cited By ~ 4

Author(s):

Nan Wang ◽

Yeting Zhang ◽

Erika Gedvilaite ◽

Jui Wan Loh ◽

Timothy Lin ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Lysosomal Storage Diseases ◽

Unknown Etiology ◽

Lysosomal Storage ◽

Storage Diseases ◽

Whole Exome ◽

Genetic Bases

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Diagnostic Whole Exome Sequencing in Patients with Short Stature

10.1101/414987 ◽

2018 ◽

Cited By ~ 1

Author(s):

Huijuan Zhu ◽

Ziying Yang ◽

Jun Sun ◽

Wei Li ◽

Hongbo Yang ◽

...

Keyword(s):

Short Stature ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Clinical Utility ◽

Molecular Diagnostic ◽

Unknown Etiology ◽

Growth Disorders ◽

Pediatric Endocrinology ◽

Genetic Causes ◽

Whole Exome

AbstractShort stature is among the most common reasons for children being referred to the pediatric endocrinology clinics. The cause of short stature is broad, in which genetic factors play a substantial role, especially in primary growth disorders. However, identifying the molecular causes for short stature remains as a challenge because of the high heterogeneity of the phenotypes. Here, whole exome sequencing (WES) was used to identify the genetic causes of short stature with unknown etiology for 20 patients aged from 1 to 16 years old. The genetic causes of short stature were identified in 9 of the 20 patients, corresponding to a molecular diagnostic rate of 45%. Notably, in 2 of the 9 patients identified with genetic causes, the diagnosed diseases based on WES are different from the original clinical diagnosis. Our results highlight the clinical utility of WES in the diagnosis of rare, high heterogeneity disorders.

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