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

2021 ◽  
Vol 7 (1) ◽  
pp. 9
Author(s):  
Kanokwan Sriwattanapong ◽  
Kitiwan Rojnueangnit ◽  
Thanakorn Theerapanon ◽  
Chalurmpon Srichomthong ◽  
Thantrira Porntaveetus ◽  
...  

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.

Dermatology ◽  
2022 ◽  
pp. 1-10
Author(s):  
Angelo Valerio Marzano ◽  
Giovanni Genovese ◽  
Chiara Moltrasio ◽  
Paola Maura Tricarico ◽  
Rossella Gratton ◽  
...  

<b><i>Background:</i></b> 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. <b><i>Objective:</i></b> To describe clinical features and genetic signature of patients with the main syndromic HS forms, i.e., PASH, PAPASH, and PASH/SAPHO overlapping. <b><i>Methods:</i></b> Whole-exome sequencing (WES) approach was performed in ten patients with syndromic HS. <b><i>Results:</i></b> 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 <i>NOD2</i> gene, two variants in <i>OTULIN</i>, and a variant in <i>GJB2</i>, respectively. Three PAPASH and three PASH/SAPHO overlapping patients who had also joint inflammation showed two different variants in <i>NCSTN</i>, one in <i>WDR1</i> and <i>PSTPIP1</i>, and two variants in <i>NLRC4</i>, one of whom was present in a patient with a mixed phenotype characterized by gut and joint inflammation. <b><i>Limitations:</i></b> Limited number of patients that can be counterbalanced by the rarity of syndromic HS. <b><i>Conclusion:</i></b> Syndromic HS can be considered as a polygenic autoinflammatory condition; currently WES is a diagnostic tool allowing more accurate genotype-phenotype correlation.


Author(s):  
SE Buerki ◽  
EB Toyota ◽  
I Guella ◽  
M McKenzie ◽  
D Evans ◽  
...  

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.


2021 ◽  
Vol 58 (S1) ◽  
pp. 1-1
Author(s):  
K.K. Haratz ◽  
A. Reches ◽  
V. Offen Glassner ◽  
J. Har‐Toov ◽  
L. Ben‐Sira ◽  
...  

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e97040 ◽  
Author(s):  
Byung Yoon Choi ◽  
Jiwoong Kim ◽  
Juyong Chung ◽  
Ah Reum Kim ◽  
Sue Jean Mun ◽  
...  

2017 ◽  
Vol 60 (12) ◽  
pp. 635-638 ◽  
Author(s):  
Ryojun Takeda ◽  
Masaki Takagi ◽  
Hiroyuki Shinohara ◽  
Hiroshi Futagawa ◽  
Satoshi Narumi ◽  
...  

2021 ◽  
Vol 13 ◽  
Author(s):  
Lin Sun ◽  
Jianye Zhang ◽  
Ning Su ◽  
Shaowei Zhang ◽  
Feng Yan ◽  
...  

Background: Sporadic dementias generally occur in older age and are highly polygenic, which indicates some patients transmitted in a poly-genes hereditary fashion.Objective: Our study aimed to analyze the correlations of genetic features with clinical symptoms in patients with degenerative dementia.Methods: We recruited a group of 84 dementia patients and conducted the whole exome sequencing (WES). The data were analyzed focusing on 153 dementia-related causing and susceptible genes.Results: According to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines, we identified four reported pathogenic variants, namely, PSEN1 c.A344G, APP c.G2149A, MAPT c.G1165A, and MAPT c.G742A, one reported likely pathogenic variant, namely, PSEN2 c.G100A, one novel pathogenic variants, SQSTM1 c.C671A, and three novel likely pathogenic variants, namely, ABCA7 c.C4690T, ATP13A2 c.3135delC, and NOS3 c.2897-2A &gt; G. 21 variants with uncertain significance in PSEN2, C9orf72, NOTCH3, ABCA7, ERBB4, GRN, MPO, SETX, SORL1, NEFH, ADCM10, and SORL1, etc., were also detected in patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD).Conclusion: The new variants in dementia-related genes indicated heterogeneity in pathogenesis and phenotype of degenerative dementia. WES could serve as an efficient diagnostic tool for detecting intractable dementia.


2020 ◽  
Vol 8 ◽  
pp. 205031212092265
Author(s):  
Adiratna Mat Ripen ◽  
Hamidah Ghani ◽  
Chai Teng Chear ◽  
Mei Yee Chiow ◽  
Sharifah Nurul Husna Syed Yahya ◽  
...  

Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients. Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed. Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing. Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.


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