Novel interstitial 2q12.3q13 microdeletion predisposes to developmental delay and behavioral problems
In this study, detailed clinical and cytogenetic data of three unrelated patients with interstitial 2q12.3q13 microdeletion were described and compared with thirteen 2q12.3q13 microdeletion patients, gathered from the medical literature and public databases. 60 Â K aCGH analysis revealed three overlapping 2q12.3q13 microdeletions measuring 1.88Â Mb in patient 1, 1.25Â Mb in patient 2, and 0.41Â Mb in patient 3, respectively. Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative real-time PCR. V ariable clinical features of 2q12.3q13 microdeletion including micr...
Source: Neurogenetics - June 16, 2021 Category: Genetics & Stem Cells Source Type: research
Pitt –Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations
AbstractPitt –Hopkins syndrome is an underdiagnosed neurodevelopmental disorder which is characterized by specific facial features, early-onset developmental delay, and moderate to severe intellectual disability. The genetic cause, a deficiency of the TCF4 gene, has been established; however, the underlying pa thological mechanisms of this disease are still unclear. Herein, we report four unrelated children with different de novo mutations (T606A, K607E, R578C, and V617I) located at highly conserved sites and with clinical phenotypes which present variable degrees of developmental delay and intellectual d isability. Thre...
Source: Neurogenetics - June 14, 2021 Category: Genetics & Stem Cells Source Type: research
Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases
AbstractParoxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 Â years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age de...
Source: Neurogenetics - June 8, 2021 Category: Genetics & Stem Cells Source Type: research
Revisiting the pathogenic mechanism of the GJB1 5 ’ UTR c.-103C  & gt;  T mutation causing CMTX1
This study assessed the internal ribosomal entry site (IRES) activity previously reported for the ratGjb1 P2 5 ’ untranslated region (UTR). Using a bicistronic assay and transfecting RT4 Schwann cells, IRES activity of the humanGJB1 P2 5 ’ UTR was compared to theGJB1 P2 5 ’ UTR containing either the c.-103C >  T mutation or the non-pathogenic c.-102G >  A variant. No differences inGJB1 P2 5 ’ UTR IRES activity were observed between the negative control, the wild-type P2 5’ UTR, the c.-103C >  T 5’ UTR or the c.-102G >  A 5’ UTR, irrespective of theGJB1 intron being present (p =â€...
Source: Neurogenetics - June 5, 2021 Category: Genetics & Stem Cells Source Type: research
Does genetic anticipation occur in familial Alexander disease?
We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent –offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon. (Source: Neurogenetics)
Source: Neurogenetics - May 28, 2021 Category: Genetics & Stem Cells Source Type: research
More evidence on TRIO missense mutations in the spectrin repeat domain causing severe developmental delay and recognizable facial dysmorphism with macrocephaly
AbstractTRIO is a Dbl family guanine nucleotide exchange factor (GEF) and an important regulator of neuronal development. Most truncating and missense variants affecting the Dbl homology domain ofTRIO are associated with a neurodevelopmental disorder with microcephaly (MIM617061). Recently, de novo missense variants affecting the spectrin repeat region of TRIO were associated with a novel phenotype comprising severe developmental delay and macrocephaly (MIM618825). Here, we provide more evidence on this newTRIO-associated phenotype by reporting two severely affected probands with de novo missense variants inTRIO affecting ...
Source: Neurogenetics - May 19, 2021 Category: Genetics & Stem Cells Source Type: research
Genotype –phenotype correlations of heterozygous HTRA1 -related cerebral small vessel disease: case report and systematic review
This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygousHTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score;p <  0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p <  0.05) presented with more ...
Source: Neurogenetics - May 8, 2021 Category: Genetics & Stem Cells Source Type: research
Dravet syndrome and Dravet syndrome-like phenotype: a systematic review of the SCN1A and PCDH19 variants
AbstractDravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients with this syndrome presentSCN1A pathogenic variants, which encodes an alpha subunit of a neural voltage-dependent sodium channel. There is a correlation betweenPCDH19 pathogenic variants, encodes the protocadherin 19, and a similar disease to DS known as DS-like phenotype. The present review aims to clarify the differences between DS and DS-like phenotype according to theSCN1A andPCDH19 variants. A systematic review was conducted in PubMed and Virtual ...
Source: Neurogenetics - May 3, 2021 Category: Genetics & Stem Cells Source Type: research
A novel pathogenic variant in the 3 ʹ end of the AGTPBP1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype?
AbstractChildhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a recently described form of the large group of infantile hereditary lower motor neuron diseases (Teoh et al. 2017), resulting from biallelic damaging variants in theAGTPBP1 gene, first described by Shashi et al. in EMBO J 37(23):e100540,2018. AGTPBP-related neurodegeneration is a severe neurodevelopmental disorder that progresses with global developmental delay and intellectual disability, often accompanied with peripheral nerve damage and lower motor degeneration and a fatal course in the early years of life. The encoded protein is ATP/GTP-Bind...
Source: Neurogenetics - April 28, 2021 Category: Genetics & Stem Cells Source Type: research
Multi-system neurological disorder associated with a CRYAB variant
We report a multiplex family with extended multisystem neurological phenotype associated with aCRYAB variant. Two affected siblings were evaluated with whole exome sequencing, muscle biopsy, laser microdissection, and mass spectrometry-based proteomic analysis. Both patients and their mother manifested a combination of early-onset cataracts, cardiomyopathy, cerebellar ataxia, optic atrophy, cognitive impairment, and myopathy. Whole exome sequencing identified a heterozygous c.458C>T variant mapped to the C-terminal extension domain of the Alpha-crystallin B chain, disrupting its function as a molecular chaperone and its...
Source: Neurogenetics - April 3, 2021 Category: Genetics & Stem Cells Source Type: research
Welcoming articles on genotype-dependent clinical features and diagnostics
(Source: Neurogenetics)
Source: Neurogenetics - April 1, 2021 Category: Genetics & Stem Cells Source Type: research
Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia
AbstractAtaxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of twoATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this f...
Source: Neurogenetics - March 29, 2021 Category: Genetics & Stem Cells Source Type: research
8p21.3 deletions are rare causes of non-syndromic autism spectrum disorder
AbstractAde novo 0.95 Mb 8p21.3 deletion had been identified in an individual with non-syndromic autism spectrum disorder (ASD) through high-resolution copy number variant analysis. Subsequent screening of in-house and publicly available databases resulted in the identification of six additional individuals with 8p21.3 deletions. Through case-based reasoning, we conclude that 8p21.3 deletions are rare causes of non-syndromic neurodevelopmental and neuropsychiatric disorders. Based on literature data, we highlight six genes within the region of minimal overlap as potential ASD genes or genes for neuropsychiatric disorders:D...
Source: Neurogenetics - March 8, 2021 Category: Genetics & Stem Cells Source Type: research
Myoclonic dystonia phenotype related to a novel calmodulin-binding transcription activator 1 sequence variant
We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novelCAMTA1 sequence variant. Furthermore, by identifying an additional, recurrentCAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated withCAMTA1 gene mutations. (Source: Neurogenetics)
Source: Neurogenetics - March 6, 2021 Category: Genetics & Stem Cells Source Type: research
De novo homozygous variant of the SCN1A gene in a patient with severe Dravet syndrome complicated by acute encephalopathy
AbstractVariants in theSCN1A gene have been identified in epilepsy patients with widely variable phenotypes and they are generally heterozygous. Here, we report a homozygous missense variant, NM_001165963.4: c.4319C>T (p.Ala1440Val), in theSCN1A gene which seemed to occur de novo together with a gene conversion event. It ’s highly possible that this variant, although located in a critical functional domain of protein Nav1.1, depending on the nature of the amino acid substitution, may not cause the complete loss of protein function. And the accumulated effect by having this variant on both alleles results in a Drav et ...
Source: Neurogenetics - March 5, 2021 Category: Genetics & Stem Cells Source Type: research
