scholarly journals FAM20C Overview: Classic and Novel Targets, Pathogenic Variants and Raine Syndrome Phenotypes

2021 ◽  
Vol 22 (15) ◽  
pp. 8039
Author(s):  
Icela Palma-Lara ◽  
Monserrat Pérez-Ramírez ◽  
Patricia García Alonso-Themann ◽  
Ana María Espinosa-García ◽  
Ricardo Godinez-Aguilar ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protein Kinase ◽  
Bone Formation ◽  
Congenital Defects ◽  
Clinical Aspects ◽  
Pathogenic Variants ◽  
Gene Coding ◽  
Raine Syndrome ◽  
Osteosclerotic Dysplasia ◽  
Novel Targets

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.

scholarly journals Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Beatrice Berti ◽  
Giovanna Longo ◽  
Francesco Mari ◽  
Stefano Doccini ◽  
Ilaria Piccolo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mitochondrial Dysfunction ◽  
Early Onset ◽  
Integrated Approach ◽  
Compound Heterozygous ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Pathogenic Variants ◽  
First Case ◽  
Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

scholarly journals A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Giada Moresco ◽  
Jole Costanza ◽  
Carlo Santaniello ◽  
Ornella Rondinone ◽  
Federico Grilli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Signs ◽  
Missense Variant ◽  
Psychomotor Development ◽  
Helicase Domain ◽  
Protein Activity ◽  
Mrna Metabolism ◽  
Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

scholarly journals NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy

2021 ◽  
Author(s):  
Patryk Lipiński ◽  
Milena Greczan ◽  
Dorota Piekutowska-Abramczuk ◽  
Elżbieta Jurkiewicz ◽  
Agnieszka Bakuła ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Pediatric Patient ◽  
Brain Atrophy ◽  
Muscular Hypotonia ◽  
Motor Delay ◽  
Pathogenic Variants

AbstractBiallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

scholarly journals Clinical characteristics of Polish patients with molecularly confirmed Mowat-Wilson syndrome

2021 ◽  
Author(s):  
Aleksandra Jakubiak ◽  
Krzysztof Szczałuba ◽  
Magdalena Badura-Stronka ◽  
Anna Kutkowska-Kaźmierczak ◽  
Anna Jakubiuk-Tomaszuk ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Congenital Anomalies ◽  
Chromosomal Region ◽  
Neurodevelopmental Disorder ◽  
Hirschsprung Disease ◽  
Psychomotor Retardation ◽  
Facial Features ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Intragenic Deletions

AbstractMowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans

2021 ◽  
Author(s):  
Nicole J Van Bergen ◽  
Katrina M Bell ◽  
Kirsty Carey ◽  
Russell Gear ◽  
Sean Massey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurological Disorders ◽  
Promoter Region ◽  
Nuclear Pore ◽  
Valuable Insight ◽  
Amino Acid Deletion ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Functional Analyses ◽  
Insight Into

Abstract The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings’ neurological disorder.

scholarly journals Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability

PLoS ONE ◽  
2018 ◽  
Vol 13 (11) ◽  
pp. e0208324 ◽  
Author(s):  
Megan McSherry ◽  
Katherine E. Masih ◽  
Nursel H. Elcioglu ◽  
Pelin Celik ◽  
Ozge Balci ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Candidate Gene ◽  
Genetic Heterogeneity ◽  
Autosomal Recessive ◽  
Pathogenic Variants

scholarly journals GENETIC ANALYSIS OF FAMILIES HAVING AUTOSOMAL RECESSIVE INTELLECTUAL DISABILITY

2019 ◽  
Vol 17 (2) ◽  
Author(s):  
Jamshed Khan ◽  
Muhammad Junaid ◽  
Shahab Uddin ◽  
Khalida Moeed ◽  
Usman Ullah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Genetic Analysis ◽  
Single Gene ◽  
Cross Sectional Study ◽  
Molecular Diagnostic ◽  
Developmental Defect ◽  
Chromosomal Disorders ◽  
Cross Sectional ◽  
Pathogenic Variants ◽  
Development Delay

Background: Intellectual disability (ID) is a neuro-developmental defect that is manifested by development delay and learning disability. Such defects may be caused due to chromosomal disorders (trisomy 18 or Down syndrome) or single gene mutation. Its worldwide prevalence is estimated to be 1-3%. The genetic etiology of non-syndromic ID is poorly understood. To date, more than 100 loci have been reported to be associated with non-syndromic ID. The objective of this study was to identify the causative genes for three Materials & Methods: This cross-sectional study was conducted in the Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan from March 2014 to August 2015. The inclusion criteria set for the families was consanguineous relation and more than two patients per family (including cousins). All the patients were tested individually in friendly atmosphere using IQ test to scale the ID on the basis of performance. Thereafter, blood samples were taken by aseptic method and DNA was extracted for the purpose of doing genetic analysis. In genetic analysis, exome sequencing was performed to find the pathogenic variants. Subsequently. Sanger sequencing was also done to see the segregation of pathogenic variants. Results: Genetic analysis found mutation in AP4B1 in Family 1, in WDR62 in Family 2, while Family 3 was unremarkable. Conclusion: The study involved genetic analysis of three consanguineous families and found mutation in AP4B1 in Family 1, in WDR62 in Family 2, while Family 3 was unremarkable. The present research will help in devising molecular diagnostic technics for pre-marital and pre-conception testing.

scholarly journals Exploring the Genotype–Phenotype Correlation in GBA-Parkinson Disease: Clinical Aspects, Biomarkers, and Potential Modifiers

2021 ◽  
Vol 12 ◽  
Author(s):  
Elisa Menozzi ◽  
Anthony H. V. Schapira
Keyword(s):  
Parkinson Disease ◽  
Progressive Disease ◽  
Clinical Aspects ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Risk Variants ◽  
Increased Risk ◽  
Severe Motor ◽  
Heterozygous Carriers

Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.

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