scholarly journals Novel Compound Heterozygous Variants of the ABCC8 Gene Warrant Identification of Pancreatic Histology in Infant with Diazoxide-unresponsive Congenital Hyperinsulinism

Children ◽  
2021 ◽  
Vol 8 (10) ◽  
pp. 836
Author(s):  
Rana Al Balwi ◽  
Dalal Bubshait ◽  
Raed Al Nefily ◽  
Omar Al Ghamdi
Keyword(s):  
Autosomal Recessive ◽  
Severe Hypoglycemia ◽  
Katp Channels ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Abcc8 Gene ◽  
Genes Encoding ◽  
One Year ◽  
The One ◽  
Compound Heterozygous Variants

Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion, resulting in severe hypoglycemia. Mutations in the ABCC8 and KCNJ11 genes encoding KATP channels in beta cells of the pancreas are common among patients with CHI. Autosomal recessive CHI with diffuse involvement is the most common type of CHI among Saudi patients. It is relatively common for patients with autosomal recessive CHI to be medically unresponsive and undergo pancreatectomy. In this case report, we describe novel compound heterozygous variants in the ABCC8 gene in a Saudi infant that caused diazoxide-unresponsive CHI. The variants included a monoallelic paternally inherited variant that has been previously reported to cause a focal form of CHI and a maternally inherited variant of unknown significance (VUS). The severity of CHI in this patient was mild over the one-year follow-up period, with a near-optimal glycemic response on a low dose of octreotide. We suspected an atypical subtype of histological involvement in the patient. In this report, we highlight the phenotypic spectrum of novel compound heterozygous variants in a patient with CHI and consider that the report can help establish the pathogenicity of the VUS.

scholarly journals An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1561
Author(s):  
Nassim Boutouchent ◽  
Julie Bourilhon ◽  
Bénédicte Sudrié-Arnaud ◽  
Antoine Bonnevalle ◽  
Lucie Guyant-Maréchal ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Late Onset ◽  
Genetic Disorder ◽  
Severe Hypoglycemia ◽  
Compound Heterozygous ◽  
Lyase Deficiency ◽  
Clinical Onset ◽  
Life Threatening ◽  
Incidental Discovery ◽  
Compound Heterozygous Variants

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.

Clinical and Pathological Features of a Newborn With Compound Heterozygous ANKS6 Variants

2019 ◽  
Vol 23 (3) ◽  
pp. 235-239
Author(s):  
Sakil Kulkarni ◽  
Brooj Abro ◽  
Maria Laura Duque Lasio ◽  
Janis Stoll ◽  
Dorothy K Grange ◽  
...  
Keyword(s):  
Cardiac Failure ◽  
Renal Dysplasia ◽  
Cardiomyocyte Hypertrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Genes Encoding ◽  
Cystic Renal Dysplasia ◽  
Cystic Renal Disease ◽  
Compound Heterozygous Variants

We report a term female infant born to nonconsanguineous parents who presented with renal failure at birth, hypothyroidism, cholestasis, and progressive cardiac dysfunction. Multigene next-generation sequencing panels for cholestasis, cardiomyopathy, and cystic renal disease did not reveal a unifying diagnosis. Whole exome sequencing revealed compound heterozygous pathogenic variants in ANKS6 (Ankyrin Repeat and Sterile Alpha Motif Domain Containing 6), which encodes a protein that interacts with other proteins of the Inv compartment of cilium ( NEK8, NPHP2/INVS, and NPHP3). ANKS6 has been shown to be important for early renal development and cardiac looping in animal models. Autopsy revealed cystic renal dysplasia and cardiomyocyte hypertrophy, disarray, and focal necrosis. Liver histology revealed cholestasis and centrilobular necrosis, which was likely a result of progressive cardiac failure. This is the first report of compound heterozygous variants in ANKS6 leading to a nephronopthisis-related ciliopathy-like phenotype. We conclude that pathogenic variants in ANKS6 may present early in life with severe renal and cardiac failure, similar to subjects with variants in genes encoding other proteins in the Inv compartment of the cilium.

scholarly journals Clinical and genetic characterization of congenital hyperinsulinism in Spain

2016 ◽  
Vol 174 (6) ◽  
pp. 717-726 ◽  
Author(s):  
R Martínez ◽  
C Fernández-Ramos ◽  
A Vela ◽  
T Velayos ◽  
A Aguayo ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Severe Hypoglycemia ◽  
Compound Heterozygous ◽  
Congenital Hyperinsulinism ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lower Blood ◽  
Design And Methods

Context Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. Objective To characterize clinically and genetically CHI patients in Spain. Design and methods We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. Results We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. Conclusions Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.

scholarly journals Identification of Novel Compound Heterozygous MYO15A Mutations in Two Chinese Families with Autosomal Recessive Nonsyndromic Hearing Loss

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Xiao-Hui Wang ◽  
Le Xie ◽  
Sen Chen ◽  
Kai Xu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Bioinformatics Analysis ◽  
Compound Heterozygous ◽  
Congenital Deafness ◽  
Chinese Families ◽  
Novel Variants ◽  
Common Causes ◽  
Compound Heterozygous Variants ◽  
Generation Sequencing

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.

scholarly journals Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong Jin ◽  
Xiaotun Ren ◽  
Husheng Wu ◽  
Yanqi Hou ◽  
Fang Fang
Keyword(s):  
Autosomal Recessive ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Protein Coding ◽  
Case Presentation ◽  
Cerebral Calcifications ◽  
Clinical Investigations ◽  
Patient Reported ◽  
Cerebral Microangiopathy ◽  
Compound Heterozygous Variants

Background: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare autosomal recessive cerebral microangiopathy. Recently, biallelic variants in a non-protein-coding gene SNORD118 have been discovered to cause LCC.Case Presentation: We here report a genetically confirmed childhood case of LCC. The patient was a 4-year-and-1-month-old boy with focal seizures. The age at onset of his seizure was 10 days after birth. The seizures were well-controlled by antiepileptic treatment but reoccurred twice due to a head impact accident and a fever, respectively. He suffered from a self-limited esotropia and unsteady running gait during the seizure onset. He had the typical neuroimaging triad of multifocal intracranial calcifications, cysts, and leukoencephalopathy. Genetic analysis indicated that he carried compound heterozygous variants of n.*9C>T and n.3C>T in SNORD118, which were inherited from his parents.Conclusion: We report a childhood LCC case with compound heterozygous variants in SNORD118. To the best of our knowledge, the patient reported in our case had the youngest onset age of LCC with a determined genotype. The triad cerebral-imaging findings of calcifications, cysts, and leukoencephalopathy provide a crucial diagnostic basis. Moreover, the gene assessment, together with the clinical investigations, should be considered for the diagnosis of LCC.

scholarly journals Compound heterozygous c.598_612del and c.1746-20C > G CAPN3 genotype cause autosomal recessive limb-girdle muscular dystrophy-1: a case report

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Evelina Siavrienė ◽  
Gunda Petraitytė ◽  
Birutė Burnytė ◽  
Aušra Morkūnienė ◽  
Violeta Mikštienė ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Autosomal Recessive ◽  
Premature Termination Codon ◽  
Limb Girdle Muscular Dystrophy ◽  
Lower Limbs ◽  
Compound Heterozygous ◽  
Targeted Next Generation Sequencing ◽  
Splicing Variant ◽  
Cdna Analysis ◽  
Compound Heterozygous Variants

Abstract Background Autosomal recessive limb–girdle muscular dystrophy-1 (LGMDR1), also known as calpainopathy, is a genetically heterogeneous disorder characterised by progression of muscle weakness. Homozygous or compound heterozygous variants in the CAPN3 gene are known genetic causes of this condition. The aim of this study was to confirm the molecular consequences of the CAPN3 variant NG_008660.1(NM_000070.3):c.1746-20C > G of an individual with suspected LGMDR1 by extensive complementary DNA (cDNA) analysis. Case presentation In the present study, we report on a male with proximal muscular weakness in his lower limbs. Compound heterozygous NM_000070.3:c.598_612del and NG_008660.1(NM_000070.3):c.1746-20C > G genotype was detected on the CAPN3 gene by targeted next-generation sequencing (NGS). To confirm the pathogenicity of the variant c.1746-20C > G, we conducted genetic analysis based on Sanger sequencing of the proband’s cDNA sample. The results revealed that this splicing variant disrupts the original 3′ splice site on intron 13, thus leading to the skipping of the DNA fragment involving exon 14 and possibly exon 15. However, the lack of exon 15 in the CAPN3 isoforms present in a blood sample was explained by cell-specific alternative splicing rather than an aberrant splicing mechanism. In silico the c.1746-20C > G splicing variant consequently resulted in frameshift and formation of a premature termination codon (NP_000061.1:p.(Glu582Aspfs*62)). Conclusions Based on the results of our study and the literature we reviewed, both c.598_612del and c.1746-20C > G variants are pathogenic and together cause LGMDR1. Therefore, extensive mRNA and/or cDNA analysis of splicing variants is critical to understand the pathogenesis of the disease.

scholarly journals Compound heterozygous variants in the ABCG8 gene in a Japanese girl with sitosterolemia

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Nobuhiro Hashimoto ◽  
Sumito Dateki ◽  
Eri Suzuki ◽  
Takatoshi Tsuchihashi ◽  
Aiko Isobe ◽  
...  
Keyword(s):  
Plant Sterol ◽  
Autosomal Recessive ◽  
Elevated Serum ◽  
Asian Population ◽  
Autosomal Recessive Disorder ◽  
Compound Heterozygous ◽  
Heterozygous State ◽  
Single Nucleotide ◽  
Compound Heterozygous Variants ◽  
Compound Heterozygous State

AbstractSitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.

Novel compound heterozygous variants in the NBAS gene in a child with osteogenesis imperfecta and recurrent acute liver failure

2021 ◽  
Vol 14 (2) ◽  
pp. e234993
Author(s):  
Sowmya Krishnan ◽  
Ankur Rughani ◽  
Anne Tsai ◽  
Sirish Palle
Keyword(s):  
Osteogenesis Imperfecta ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Autosomal Recessive ◽  
Retrograde Transport ◽  
Compound Heterozygous ◽  
X Rays ◽  
Multiple Fractures ◽  
Therapeutic Implications ◽  
Compound Heterozygous Variants

Osteogenesis imperfecta (OI) consists of a group of genetically and phenotypically heterogeneous diseases characterised by bone fragility. Recent improvement in gene sequencing methods has helped us identify rare forms of OI that are inherited in an autosomal recessive manner. Paediatric endocrinology was consulted on a newborn girl with multiple fractures and wavy thin ribs noted on X-rays. In addition to the bone phenotype, she also has short stature and recurrent acute liver failure (ALF) episodes triggered by intercurrent illness. Whole exome sequencing revealed two novel compound heterozygous variants in neuroblastoma amplified sequence (NBAS) gene. NBAS gene codes for a protein that is involved in nonsense-mediated decay pathway and retrograde transport of proteins from Golgi to endoplasmic reticulum. Recognition of pathogenic variants in this gene as a rare cause of autosomal recessive OI and recurrent ALF has important therapeutic implications.

Sign in / Sign up

Export Citation Format

Share Document