OC01.02: Genotype‐phenotype correlation in fetuses with major brain malformations using whole‐exome sequencing

Background: The genetics of syndromic hidradenitis suppurativa (HS), an immune-mediated condition associated with systemic comorbidities such as inflammatory bowel diseases and arthritis, has not been completely elucidated. Objective: To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. Methods: Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. Results: Three clinical settings have been identified based on presence/absence of gut and joint inflammation. Four PASH patients who had also gut inflammation showed three different variants in NOD2 gene, two variants in OTULIN, and a variant in GJB2, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in NCSTN, one in WDR1 and PSTPIP1, and two variants in NLRC4, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. Limitations: Limited number of patients that can be counterbalanced by the rarity of syndromic HS. Conclusion: Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.

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Compound Heterozygosity for a Novel Frameshift Variant Causing Fatal Infantile Liver Failure and Genotype–Phenotype Correlation of POLG c.3286C>T Variant

International Journal of Neonatal Screening ◽

10.3390/ijns7010009 ◽

2021 ◽

Vol 7 (1) ◽

pp. 9

Author(s):

Kanokwan Sriwattanapong ◽

Kitiwan Rojnueangnit ◽

Thanakorn Theerapanon ◽

Chalurmpon Srichomthong ◽

Thantrira Porntaveetus ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Disease Onset ◽

Definitive Treatment ◽

Compound Heterozygous ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation ◽

Whole Exome ◽

Polg Gene ◽

Standards And Guidelines

A variant in the POLG gene is the leading cause of a heterogeneous group of mitochondrial disorders. No definitive treatment is currently available. Prenatal and newborn screening have the potential to improve clinical outcome of patients affected with POLG-related disorders. We reported a 4-month-old infant who presented with developmental delay, fever, and diarrhea. Within two weeks after hospital admission, the patient developed hepatic failure and died. Liver necropsy demonstrated an extensive loss of hepatocytes and bile duct proliferations. Trio-whole exome sequencing identified that the patient was compound heterozygous for a novel frameshift variant c.3102delG (p.Lys1035Serfs*59) and a common variant c.3286C>T (p.Arg1096Cys) in POLG (NM_002693.3) inherited from the mother and father, respectively. The c.3102delG (p.Lys1035Serfs*59) was a null variant and classified as pathogenic according to the American College of Medical Genetics and Genomics Standards and Guidelines. Prenatal genetic screenings using rapid whole exome sequencing successfully detected the heterozygous c.3286C>T variant in the following pregnancy and the normal alleles in the other one. Both children had been healthy. We reviewed all 34 cases identified with the POLG c.3286C>T variant and found that all 15 compound heterozygous cases had two missense variants except our patient who had the truncating variant and showed the earliest disease onset, rapid deterioration, and the youngest death. All homozygous cases had disease onset before age 2 and developed seizure. Here, we report a novel POLG variant expanding the genotypic spectrum, demonstrate the successful use of exome sequencing for prenatal and neonatal screenings of POLG-related disorders, and show the genotype–phenotype correlation of the common c.3286C>T variant.

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A.01 Targeted analysis of whole exome sequencing and genotype-phenotype correlation in epileptic encephalopathies

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2016.53 ◽

2016 ◽

Vol 43 (S2) ◽

pp. S7-S7

Author(s):

SE Buerki ◽

EB Toyota ◽

I Guella ◽

M McKenzie ◽

D Evans ◽

...

Keyword(s):

Next Generation Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Next Generation ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation ◽

Whole Exome ◽

Generation Sequencing

Background: Epileptic encephalopathy (EE) is a severe condition in which epileptic activity itself may contribute to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology alone. Next generation sequencing technologies such as whole exome sequencing (WES) can detect underlying genetic causes of in EE. Methods: This report describes genotype-phenotype correlation of 29 subjects with unexplained epileptic encephalopathy, in whom WES, targeting a list of 557 epilepsy-associated genes was performed. Epilepsy phenotyping was done according to current ILAE recommendations. Results: Median age at seizure onset was 14 months (range 1-48). Electroclinical syndromes were applicable for 16/29, 8/16 had a definite/likely diagnosis. 6/8 subjects with West syndrome had variants in ALG13, STXBP1, PAFAH1B1, SLC35A2, CDKL5 and ADSL. 2 patients with Dravet syndrome had variants in SCN1A and PCDH19 respectively. 4/29 had unspecified EE and definite/likely diagnosis due to STXBP1, POLG, and KCNQ2 (2) variants. 4/29 had a possible diagnosis involving GABRB3, ARHGEF9, PCDH19 and SCN3A variants. Conclusions: The high diagnostic yield (definite/likely diagnosis in 11/29 = 38%), involving a broad variety of epilepsy-associated genes in different electroclinical syndromes justifies the diagnostic approach of early onset EE by next generation sequencing.

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Whole-Exome Sequencing Identifies a Novel Genotype-Phenotype Correlation in the Entactin Domain of the Known Deafness Gene TECTA

PLoS ONE ◽

10.1371/journal.pone.0097040 ◽

2014 ◽

Vol 9 (5) ◽

pp. e97040 ◽

Cited By ~ 8

Author(s):

Byung Yoon Choi ◽

Jiwoong Kim ◽

Juyong Chung ◽

Ah Reum Kim ◽

Sue Jean Mun ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Phenotype Correlation ◽

Deafness Gene ◽

Genotype Phenotype Correlation ◽

Whole Exome ◽

Novel Genotype

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Faculty Opinions recommendation of Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5376956.9620054 ◽

2011 ◽

Author(s):

David Glahn

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Brain Malformations

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A Novel Variant of SMARCB1 in Rare Familial Schwannomatosis Identified by Whole-Exome Sequencing and Genotype-Phenotype Correlation Analysis.

10.21203/rs.3.rs-1157679/v1 ◽

2021 ◽

Author(s):

Conghui Wang ◽

Yuqiong Chai ◽

Xuechao Zhao ◽

Qianqian Li ◽

Chen Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Suppressor Gene ◽

Loss Of Function ◽

Phenotype Correlation ◽

Rhabdoid Tumour ◽

Whole Exome ◽

Mutation Database ◽

Novel Variant ◽

Autosomal Dominant Inheritance Pattern

Abstract Background: Variants in the tumor suppressor gene SMARCB1 could cause different conditions. In some cases, germline and somatic variants in SMARCB1 are implemented in schwannomatosis. But the genotype and phenotype correlation for variants in SMARCB1 has not been determined.Methods: A Chinese schwannomatosis family with an autosomal dominant inheritance pattern was recruited. Whole-exome sequencing (WES) was performed to discover the causative variant, followed by Sanger sequencing. We evaluated the Human Gene Mutation Database (HGMD) regarding SMARCB1 variants and validated associated phenotype records to assess phenotype-genotype relationships. Results: A novel deletion variant c.885_896delGAAGCTGTGCTC p.(295_299del） in SMARCB1 was identified in the affected family members and cosegregated with phenotypes in the pedigree. About 51.1% of variants in SMARCB1 located in Snf5 subunit, 80.7% of variants were loss-of-function (LOF) variants, and more variants located in the Snf5 subunit of SMARCB1 in Rhabdoid tumour (67.8%) than that in schwannomatosis (25.7%).Conclusions: Our study expands the variant spectrum of SMARCB1 and the genetic background of schwannomatosis, confirms the clinical indications for genetic screening of the SMARCB1 gene, and has implications for genetic counseling in this disease.

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