scholarly journals De Novo Nonsense Variant in ASXL3 in a Chinese Girl Causing Bainbridge–Ropers Syndrome: A Case Report and Review of Literature

2021 ◽  
Author(s):  
Qin Wang ◽  
Jianming Zhang ◽  
Nan Jiang ◽  
Jiansheng Xie ◽  
Jingxin Yang ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Developmental Delay ◽  
Sanger Sequencing ◽  
De Novo ◽  
Clinical Symptoms ◽  
Failure To Thrive ◽  
Varus Deformity ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Chinese Girl

Abstract Background: Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay. BRPS is caused by heterozygous loss-of function (LOF) variants in the additional sex combs-like 3 (ASXL3) gene which are mostly located in two mutational cluster regions (MCR). Due to the limited specific recognizable features and overlapping symptoms with Bohring–Opitz syndrome, clinical diagnosis of BRPS is challenging. Case presentation: In this study, a 2-year-8-month-old Chinese girl was referred for genetic evaluation of severe developmental delay. Reduced fetal movement was found during antenatal period and bilateral varus deformity of feet was observed at birth. Whole exome sequencing and Sanger sequencing were used to detect and confirm the variant. A novel nonsense variant c.1063G>T (p.E355X) in the ASXL3 gene (NM_030632.3) was identified in the proband and the clinical symptoms were compatible with BRPS. The parents were physical and genetic normal and prenatal diagnosis was requested for her pregnant mother with a negative Sanger sequencing result. Conclusion: The study revealed a de novo LOF variant in the ASXL3 gene and expanded the mutation spectrum for this clinical condition. By performing a literature review, we analyzed the clinical phenotype with limited fetal features and summarized genetic results of all BPRSs reported so far. More cases study may help to elucidate the function of ASXL3 gene that may be critical to understand the genetic etiology of this syndrome and assist in accurate genetic counselling, informed decision making and prenatal diagnosis.

scholarly journals A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: a case report

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110583
Author(s):  
Tong Qiu ◽  
Qian Dai ◽  
Qiu Wang
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
De Novo ◽  
Clinical Symptoms ◽  
Genetic Diagnosis ◽  
Epileptic Seizures ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Severe Intellectual Disability

ARHGEF9 encodes collybistin, a brain-specific guanosine diphosphate-guanosine-5′-triphosphate exchange factor that plays an important role in clustering of gephyrin and γ-aminobutyric acid type A receptors in the postsynaptic membrane. Overwhelming evidence suggests that defects in this protein can cause X-linked intellectual disability, which comprises a series of clinical phenotypes, including autism spectrum disorder, behavior disorder, intellectual disability, and febrile seizures. Here, we report a boy with clinical symptoms of severe intellectual disability, epilepsy, and developmental delay and regression. Trio exome sequencing ( trio-clinical exome sequencing) identified a novel hemizygous deletion, c.656_c.669delACTTCTTTGAGGCC (p. His219Leu fs*9), in exon 5 of ARHGEF9. This variant was not reported in either the Genome Aggregation Database or our database of 309 patients with neurodevelopmental disorders. Oxcarbazepine and levetiracetam reduced the frequency of the patient’s epileptic seizures to a certain extent, but psychomotor developmental delay and developmental regression became more obvious with age. This case study seeks to report a de novo loss-of-function mutation of ARHGEF9, aiming to emphasize the genetic diagnosis of X-linked intellectual disability and further improve knowledge of the ethnic distribution of ARHGEF9 mutations.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

scholarly journals Genetic analysis of 62 Chinese families with Duchenne muscular dystrophy and strategies of prenatal diagnosis in a single center

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jingjing Zhang ◽  
Dingyuan Ma ◽  
Gang Liu ◽  
Yuguo Wang ◽  
An Liu ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
De Novo ◽  
Clinical Symptoms ◽  
Perinatal Care ◽  
Genetic Diagnosis ◽  
Point Mutations ◽  
Inherited Disease ◽  
Positive Results

Abstract Background Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder. Patients with DMD usually have severe and fatal symptoms, including progressive irreversible muscle weakness and atrophy complicated with gastrocnemius muscle pseudohypertrophy. DMD is caused by mutations in the dystrophin-encoding DMD gene, including large rearrangements and point mutations. This retrospective study was aimed at supplying information on our 4-year clinical experience of DMD genetic and prenatal diagnosis at the Department of Prenatal Diagnosis in Women’s Hospital of Nanjing Medical University. Methods Multiplex ligation-dependent probe amplification (MLPA) was used to detect the exon deletions or duplications. And Ion AmpliSeq™ panel for inherited disease was used as the next-generation sequencing (NGS) method to identify the point mutations in exons of DMD gene, but the introns were not sequenced. Results In this study, the large deletions and duplications of DMD gene were detected in 32 (51.6%) of the 62 families, while point mutations were detected in 20 families (32.3%). The remaining 10 families with a negative genetic diagnosis need to be reevaluated for clinical symptoms or be detected by other molecular methods. Notably, six novel mutations were identified, including c.412A > T(p.Lys138*), c.2962delT(p.Ser988Leufs*16), c.6850dupA (p.Ser2284Lysfs*7), c.5139dupA (p.Glu 1714Argfs*5), c.6201_6203delGCCins CCCA(p.Val2069Cysfs*14) and c.10705A > T (p.Lys3569*). In 52 families with positive results, 45 mothers (86.5%) showed positive results during carrier testing and de novo mutations arose in 7 probands. The prenatal diagnosis was offered to 34 fetuses whether the pregnant mother was a carrier or not. As a result, eight male fetuses were affected, three female fetuses were carriers, and the remaining fetuses had no pathogenic mutation. Conclusions This study reported that MLPA and NGS could be used for screening the DMD gene mutations. Furthermore, the stepwise procedure of prenatal diagnosis of DMD gene was shown in our study, which is important for assessing the mutation type of fetuses and providing perinatal care in DMD high-risk families.

scholarly journals Clinical, genetic, and molecular characterization of hyperphosphatasia with mental retardation: a case report and literature review

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Layal Abi Farraj ◽  
Wassim Daoud Khatoun ◽  
Naji Abou Chebel ◽  
Victor Wakim ◽  
Katia Dawali ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Developmental Delay ◽  
Novel Mutation ◽  
Blood Levels ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

Abstract Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is a recessive disorder characterized by high blood levels of alkaline phosphatase together with typical dysmorphic signs such as cleft palate, intellectual disability, cardiac abnormalities, and developmental delay. Genes involved in the glycosylphosphatidylinositol pathway and known to be mutated in HPMRS have never been characterized in the Lebanese population. Case presentation Herein, we describe a pair of monozygotic twins presenting with severe intellectual disability, distinct facial dysmorphism, developmental delay, and increased alkaline phosphatase level. Two individuals underwent whole exome sequencing followed by Sanger sequencing to confirm the co-segregation of the mutation in the consanguineous family. A biallelic loss of function mutation in PGAP3 was detected. Both patients were homozygous for the c.203delC (p.C68LfsX88) mutation and the parents were carriers confirming the founder effect of the mutation. High ALP serum levels confirmed the molecular diagnosis. Conclusion Our findings have illustrated the genomic profile of PGAP3-related HPMRS which is essential for targeted molecular and genetic testing. Moreover, we found previously unreported clinical findings such as hypodontia and skin hyperpigmentation. These features, together with the novel mutation expand the phenotypic and genotypic spectrum of this rare recessive disorder.

Cleft Lip Palate in a Patient with 5q14.3 Deletion Syndrome: A Possible Unreported Feature?

2022 ◽  
pp. 1-8
Author(s):  
Liliana Fernández Hernández ◽  
Miguel A. Alcántara Ortigoza ◽  
Sandra E. Ramos Angeles ◽  
Ariadna González-del Angel
Keyword(s):  
Intellectual Disability ◽  
Sanger Sequencing ◽  
Cleft Lip ◽  
De Novo ◽  
Deletion Syndrome ◽  
Facial Dysmorphism ◽  
Brain Malformations ◽  
Bilateral Cleft Lip ◽  
Cleft Lip Palate ◽  
Distinctive Phenotype

5q14.3 deletion syndrome (MIM#613443) is an uncommon but well-known syndrome characterized by intellectual disability, epilepsy, hypotonia, brain malformations, and facial dysmorphism. Most patients with this syndrome have lost one copy of the <i>MEF2C</i> gene (MIM*600662), whose haploinsufficiency is considered to be responsible for the distinctive phenotype. To date, nearly 40 cases have been reported; the deletion size and clinical spectrum are variable, and at least 6 cases without <i>MEF2C</i> involvement have been documented. We herein report the clinical and cytogenomic findings of an 11-year-old girl who has a 5q14.3q21.1 de novo deletion that does not involve <i>MEF2C</i> but shares the clinical features described in other reported patients. Moreover, she additionally presents with bilateral cleft-lip palate (CLP), which has not been previously reported as a feature of the syndrome. The most frequent syndromic forms of CLP were ruled out in our patient mainly by clinical examination, and Sanger sequencing was performed to discard the presence of a <i>TBX22</i> gene (MIM*300307) defect. Our report suggests CLP as a possible unreported feature and redefines the critical phenotypic regions of 5q14.3 deletion syndrome.

scholarly journals Cerebral White Matter Lesions and Dysmorphisms: Signs Suggestive of 6p25 Deletion Syndrome—Literature Review

2019 ◽  
Vol 08 (04) ◽  
pp. 205-211
Author(s):  
Piero Pavone ◽  
Simona Domenica Marino ◽  
Giovanni Corsello ◽  
Martino Ruggieri ◽  
Danilo Castellano Chiodo ◽  
...  
Keyword(s):  
White Matter ◽  
Developmental Delay ◽  
De Novo ◽  
Clinical Manifestations ◽  
Deletion Syndrome ◽  
Cerebral White Matter ◽  
Comparative Genomic ◽  
Facial Dysmorphism ◽  
Perivascular Spaces ◽  
Renal Malformations

AbstractDeletion of the region including chromosome 6p25 has been defined as a syndrome, with more than 68 reported cases. Individuals affected by the syndrome exhibit variable findings, including developmental delay and intellectual disability, cardiac anomalies, dysmorphic features, and—less commonly—skeletal and renal malformations. Ocular and hearing abnormalities are the most notable presenting features. The region encompasses more than 15 genes, of which the FOX group is the most likely causal factor of the clinical manifestations. We report the case of a 2-year-old child with developmental delay, generalized hypotonia, facial dysmorphism, and anomalies involving malformations of the eyes, heart, teeth, and skeleton. The magnetic resonance imaging (MRI) of the child's brain displayed cerebral anomalies involving the white matter, perivascular spaces, and corpus callosum. Array-CGH (comparative genomic hybridization) analysis displayed a de novo partial deletion of the short arm of chromosome 6, extending 5.13 Mb from nt 407.231 to nt 5.541.179. In infancy, neuroradiologic findings of abnormalities in the cerebral white matter and other neurologic anomalies elsewhere in the brain, in association with dysmorphisms and malformations, are highly suggestive of the diagnosis of 6p25 deletion syndrome. When these anomalies are found, the syndrome must be included in the differential diagnosis of disorders affecting the cerebral white matter.

Sign in / Sign up

Export Citation Format

Share Document