scholarly journals MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Shinsuke Onuma ◽  
Tamaki Wada ◽  
Ryosuke Araki ◽  
Kazuko Wada ◽  
Kanako Tanase-Nakao ◽  
...  
Keyword(s):  
Japanese Patient ◽  
De Novo ◽  
Missense Variant ◽  
Phenotype Correlation ◽  
Gain Of Function ◽  
Limited Knowledge ◽  
Genotype Phenotype Correlation ◽  
Adrenal Hypoplasia

AbstractMIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype–phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p.Ala1479Ser).

scholarly journals A p.Arg499His mutation in SPAST is associated with infantile-onset complicated spastic paraplegia: a case report and review of the literature

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Haitian Nan ◽  
Hiroshi Shiraku ◽  
Tomoko Mizuno ◽  
Yoshihisa Takiyama
Keyword(s):  
Japanese Patient ◽  
De Novo ◽  
Complex Form ◽  
Review Of The Literature ◽  
Spastic Paraplegia ◽  
Phenotype Correlation ◽  
Spastic Paralysis ◽  
Hereditary Spastic Paraplegias ◽  
Genotype Phenotype Correlation ◽  
Complicated Form

Abstract Background Spastic paraplegia type 4 (SPG4) is caused by mutations in the SPAST gene, is the most common form of autosomal-dominant pure hereditary spastic paraplegias (HSP), and is rarely associated with a complicated form that includes ataxia, epilepsy, and cognitive decline. To date, the genotype-phenotype correlation has not been substantially established for SPAST mutations. Case presentation We present a Japanese patient with infantile-onset HSP and a complex form with coexisting ataxia and epilepsy. The sequencing of SPAST revealed a de novo c.1496G > A (p.R499H) mutation. A review of the literature revealed 16 additional patients with p.R499H mutations in SPAST associated with an early-onset complicated form of HSP. We found that the complicated phenotype of patients with p.Arg499His mutations could be mainly divided into three subgroups: (1) infantile-onset ascending hereditary spastic paralysis, (2) HSP with severe dystonia, and (3) HSP with cognitive impairment. Moreover, the c.1496G > A mutation in SPAST may occur as a de novo variant at noticeably high rates. Conclusion We reviewed the clinical features of the patients reported in the literature with the p.Arg499His mutation in SPAST and described the case of a Japanese patient with this mutation presenting a new complicated form. Accumulating evidence suggests a possible association between infantile-onset complicated HSP and the p.Arg499His mutation in SPAST. The findings of this study may expand the clinical spectrum of the p.Arg499His mutation in SPAST and provide an opportunity to further study the genotype-phenotype correlation of SPG4.

scholarly journals Clinical Manifestations in a Girl with NAA10-Related Syndrome and Genotype–Phenotype Correlation in Females

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 900
Author(s):  
Ilenia Maini ◽  
Stefano G. Caraffi ◽  
Francesca Peluso ◽  
Lara Valeri ◽  
Davide Nicoli ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Manifestations ◽  
Growth Failure ◽  
Autistic Traits ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Young Female ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Clinical Description

Since 2011, eight males with an X-linked recessive disorder (Ogden syndrome, MIM #300855) associated with the same missense variant p.(Ser37Pro) in the NAA10 gene have been described. After the advent of whole exome sequencing, many NAA10 variants have been reported as causative of syndromic or non-syndromic intellectual disability in both males and females. The NAA10 gene lies in the Xq28 region and encodes the catalytic subunit of the major N-terminal acetyltransferase complex NatA, which acetylates almost half the human proteome. Here, we present a young female carrying a de novo NAA10 [NM_003491:c.247C > T, p.(Arg83Cys)] variant. The 18-year-old girl has severely delayed motor and language development, autistic traits, postnatal growth failure, facial dysmorphisms, interventricular septal defect, neuroimaging anomalies and epilepsy. Our attempt is to expand and compare genotype–phenotype correlation in females with NAA10-related syndrome. A detailed clinical description could have relevant consequences for the clinical management of known and newly identified individuals.

scholarly journals X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽  
2021 ◽  
Vol 17 (6) ◽  
pp. e1009608
Author(s):  
Jia-Hui Sun ◽  
Jiang Chen ◽  
Fernando Eduardo Ayala Valenzuela ◽  
Carolyn Brown ◽  
Diane Masser-Frye ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Prolonged Exposure ◽  
De Novo ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Decay Kinetics ◽  
Gain Of Function ◽  
Ca1 Neurons ◽  
Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

scholarly journals A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiji Guo ◽  
Xia Fang ◽  
Hailei Mao ◽  
Bin Sun ◽  
Jiateng Zhou ◽  
...  
Keyword(s):  
Limb Development ◽  
Missense Variant ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Mutation Site ◽  
Genotype Phenotype Correlation ◽  
Α Helix ◽  
Severe Degree ◽  
Hands And Feet

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

scholarly journals Deciphering the Invdupdel(8p) Genotype–Phenotype Correlation: Our Opinion

2020 ◽  
Vol 10 (7) ◽  
pp. 451
Author(s):  
Manuela Lo Bianco ◽  
Davide Vecchio ◽  
Tiziana A. Timpanaro ◽  
Alessia Arena ◽  
Marina Macchiaiolo ◽  
...  
Keyword(s):  
Chromosomal Rearrangement ◽  
Scientific Literature ◽  
De Novo ◽  
Congenital Defects ◽  
Phenotype Correlation ◽  
Intermediate Area ◽  
Neurodevelopmental Delay ◽  
Skeletal Malformations ◽  
Genotype Phenotype Correlation ◽  
Inverted Duplication

The 8p inverted duplication/deletion is a rare chromosomal rearrangement clinically featuring neurodevelopmental delay, mild to severe cognitive impairment, heart congenital defects and brain abnormalities. Patients affected also present typical facial dysmorphisms and skeletal malformations, and it is thought that the composite clinical picture may fall into the chromosomal rearrangement architecture. With the major aim of better framing its related clinical and diagnostic paths, we describe a patient carrying a de novo invdupde[8p] whose clinical features have not been described so far. Hence, through an extensive genotype–phenotype correlation analysis and by reviewing the dedicated scientific literature, we compared our patient’s features with those reported in other patients, which allows us to place our proband’s expressiveness in an intermediate area, widening the scope of the already known invdupde[8p] genotype–phenotype relationship.

scholarly journals Characterization of Spectrum, de novo Rate and Genotype-Phenotype Correlation of Dominant GJB2 Mutations in Chinese Hans

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e100483 ◽  
Author(s):  
Xiuhong Pang ◽  
Yongchuan Chai ◽  
Lianhua Sun ◽  
Dongye Chen ◽  
Ying Chen ◽  
...  
Keyword(s):  
De Novo ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Gjb2 Mutations

scholarly journals STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ori Scott ◽  
Kyle Lindsay ◽  
Steven Erwood ◽  
Antonio Mollica ◽  
Chaim M. Roifman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Signature ◽  
Serum Starvation ◽  
Phenotype Correlation ◽  
Transcriptional Responses ◽  
Gain Of Function ◽  
Immune Disorder ◽  
Base Editing ◽  
Genotype Phenotype Correlation ◽  
Gene Expression Studies

AbstractSignal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype–phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype–phenotype correlation and enhancing our understanding of disease pathogenesis.

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