scholarly journals A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns

2021 ◽  
Author(s):  
Ev‐Christin Heide ◽  
Oliver Puk ◽  
Saskia Biskup ◽  
Arne Krahn ◽  
Erik Rauf ◽  
...  
Keyword(s):  
Missense Variant ◽  
Neurodevelopmental Delay ◽  
Variable Expressivity

scholarly journals Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 706
Author(s):  
Angela Sparago ◽  
Flavia Cerrato ◽  
Laura Pignata ◽  
Francisco Cammarata-Scalisi ◽  
Livia Garavelli ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Missense Variant ◽  
Abdominal Wall Defects ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Molecular Defects ◽  
Variable Expressivity ◽  
Imprinting Disorder ◽  
Perinatal Lethality ◽  
Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

Bi-allelic mutations in TRAPPC2L result in a neurodevelopmental disorder and have an impact on RAB11 in fibroblasts

2018 ◽  
Vol 55 (11) ◽  
pp. 753-764 ◽  
Author(s):  
Miroslav P Milev ◽  
Claudio Graziano ◽  
Daniela Karall ◽  
Willemijn F E Kuper ◽  
Noraldin Al-Deri ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Membrane Trafficking ◽  
Neurodevelopmental Disorder ◽  
Febrile Illness ◽  
Missense Variant ◽  
Energy Status ◽  
Protein Protein Interactions ◽  
Neurodevelopmental Delay ◽  
Pathogenic Variants ◽  
Similar Phenotype

BackgroundThe combination of febrile illness-induced encephalopathy and rhabdomyolysis has thus far only been described in disorders that affect cellular energy status. In the absence of specific metabolic abnormalities, diagnosis can be challenging.ObjectiveThe objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented clinically with a similar phenotype that included neurodevelopmental delay, febrile illness-induced encephalopathy and episodes of rhabdomyolysis, followed by developmental arrest, epilepsy and tetraplegia.MethodsWhole exome sequencing was used to identify pathogenic variants in the two individuals. Biochemical and cell biological analyses were performed on fibroblasts from these individuals and a yeast two-hybrid analysis was used to assess protein-protein interactions.ResultsProbands shared a homozygous TRAPPC2L variant (c.109G>T) resulting in a p.Asp37Tyr missense variant. TRAPPC2L is a component of transport protein particle (TRAPP), a group of multisubunit complexes that function in membrane traffic and autophagy. Studies in patient fibroblasts as well as in a yeast system showed that the p.Asp37Tyr protein was present but not functional and resulted in specific membrane trafficking delays. The human missense mutation and the analogous mutation in the yeast homologue Tca17 ablated the interaction between TRAPPC2L and TRAPPC10/Trs130, a component of the TRAPP II complex. Since TRAPP II activates the GTPase RAB11, we examined the activation state of this protein and found increased levels of the active RAB, correlating with changes in its cellular morphology.ConclusionsOur study implicates a RAB11 pathway in the aetiology of the TRAPPC2L disorder and has implications for other TRAPP-related disorders with similar phenotypes.

A Further Case of Larsen's Syndrome: Clinical and Genotypic Challenges in Diagnosis

2020 ◽  
Author(s):  
Veronica Arora ◽  
Swasti Pal ◽  
Samarth Kulshreshtha ◽  
Ishwar C. Verma
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Genetic Diagnosis ◽  
Missense Variant ◽  
Protein Modelling ◽  
Variable Expressivity ◽  
Craniofacial Dysmorphism

AbstractLarsen's syndrome is characterized by dislocation of multiple large joints, digital anomalies, craniofacial dysmorphism, and short stature. In this paper, we describe a case of a 5-month-old boy with a triad of cardinal features in association with other signs. The diagnosis was confirmed by exome sequencing, which led to the identification of a novel missense variant NM_001457.4:c.4928C > G (p.Ala1643Gly) in the FLNB gene. We describe the role of protein modelling for the establishment of pathogenicity of this variant. We also outline the challenges in genetic diagnosis due to variable expressivity of the variant and discuss the clinicogenetic profile of previously reported patients with Larsen's syndrome in India.

scholarly journals Partial Lipodystrophy and LMNA p.R545H Variant

2021 ◽  
Vol 10 (5) ◽  
pp. 1142
Author(s):  
Silvia Magno ◽  
Giovanni Ceccarini ◽  
Andrea Barison ◽  
Iacopo Fabiani ◽  
Alessandro Giacomina ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Subcutaneous Fat ◽  
Gene Mutations ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Fat Distribution ◽  
Incomplete Penetrance ◽  
Partial Lipodystrophy ◽  
Variable Expressivity ◽  
Organ Systems

Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

scholarly journals Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide

2018 ◽  
Vol 28 (11) ◽  
pp. 251-255 ◽  
Author(s):  
Sonal Singh ◽  
Zhiying Wang ◽  
Mohamed H. Shahin ◽  
Taimour Y. Langaee ◽  
Yan Gong ◽  
...  
Keyword(s):  
Missense Variant ◽  
Targeted Sequencing ◽  
Antihypertensive Response

scholarly journals Neurodevelopmental delay in the severely ill

1999 ◽  
Vol 174 (6) ◽  
pp. 563-563 ◽  
Author(s):  
P. McConville ◽  
N. Walker
Keyword(s):  
Neurodevelopmental Delay

scholarly journals L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 682
Author(s):  
Matthias Christen ◽  
Nils Janzen ◽  
Anne Fraser ◽  
Adrian C. Sewell ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Missense Variant ◽  
Microcytic Anemia ◽  
Abnormal Behavior ◽  
Functional Candidate Gene ◽  
History Of ◽  
The Brain ◽  
Hydroxyglutaric Acid

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

scholarly journals GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucas D. Ward ◽  
Ho-Chou Tu ◽  
Chelsea B. Quenneville ◽  
Shira Tsour ◽  
Alexander O. Flynn-Carroll ◽  
...  
Keyword(s):  
Bile Duct ◽  
Extrahepatic Bile Duct ◽  
Association Studies ◽  
Missense Variant ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Extrahepatic Bile Duct Cancer ◽  
Hepatocellular Damage ◽  
Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

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