DISEASE:KEGG:H00773
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Publication
Journal: Frontiers in Genetics
December/5/2019
Abstract
Autosomal dominant mental retardation-7 (MRD7) is a rare anomaly, characterized by severe intellectual disability, feeding difficulties, behavior abnormalities, and distinctive facial features, including microcephaly, deep-set eyes, large simple ears, and a pointed or bulbous nasal tip. Some studies show that the disorder has a close correlation with variants in DYRK1A. Herein we described a Chinese girl presenting typical clinical features diagnosed at 4 years old. Whole-exome sequencing of the familial genomic DNA identified a novel mutation c.930C > A (p.Tyr310*) in exon 7 of DYRK1A in the proband. The nonsense mutation was predicted to render the truncation of the protein. Our results suggested that the de novo heterozygous mutation in DYRK1A was responsible for the MRD7 in this Chinese family, which both extended the knowledge of mutation spectrum in MRD7 patients and highlighted the clinical application of exome sequencing.
Publication
Journal: Chinese Journal of Medical Genetics
May/30/2020
Abstract
Objective: To investigate the clinical and genetic features of a Chinese girl featuring mental retardation, intellectual disability, language development delay and epilepsy.
Methods: G-banded chromosomal karyotyping was carried out for the child. Genomic DNA of the patient and her parents was extracted and subjected to high-throughput sequencing. The results were analyzed with bioinformatic tools and validated by Sanger sequencing.
Results: The karyotype of the child was ascertained as 46,XX. Sequencing result showed that she has carried a de novo heterozygous c.1861C>T (p.R621X) variant of the SYNGAP1 gene.
Conclusion: The nonsense variant c.1861C>T (p.R621X) of the SYNGAP1 gene probably underlies the disease in this child. Above result has enabled genetic diagnosis and counseling for her family.
Publication
Journal: Chinese Journal of Medical Genetics
June/6/2021
Abstract
Objective: To explore the genetic basis for a child featuring global developmental delay.
Methods: DNA was extracted from peripheral blood sample taken from the patient and subjected to whole exome sequencing. Suspected variants were verified by Sanger sequencing of his family members.
Results: A heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene was detected in the proband, which was a verified to be de novo in origin.
Conclusion: The heterozygous c.239T>C (p.Ile80Thr) variant of the GNB1 gene probably underlay the disease in this child.
Publication
Journal: Revista de Neurologia
December/10/2019
Abstract
The aetiology of autosomal dominant mental retardation type 1, also known as pseudo-Angelman, MBD5-associated neurodevelopmental disorder or MBD5 haploinsufficiency, lies in a microdeletion of chromosome 2q23.1 or in a specific alteration of the MBD5 gene, which constitutes the minimum region affected in the aforementioned microdeletion.To report the case of a girl with a heterozygous de novo mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria.We report the case of an 8-year-old girl who was submitted to a developmental follow-up from the age of 18 months after presenting the association of severe intellectual disability and motor delay, lack of language development, segmental hypotonia, a wide forehead and kyphoscoliosis. Magnetic resonance imaging of the brain revealed the presence of a bilateral band heterotopia and parietooccipital polymicrogiria predominant on the left side. In the exome the de novo heterozygous variant c.397+1G>C was detected in the MBD5 gene.This is the first observation of a heterozygous mutation in the MBD5 gene associated with a neuronal migration disorder.
Publication
Journal: International Medical Case Reports Journal
October/28/2020
Abstract
The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27-51 years), while the majority was infant or adolescent (range: 0-20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.
Keywords: CTNNB1; NEDSDV; autism; distal spastic tetraparesis; heterozygous splice site variant; intellectual disability.
Publication
Journal: Seizure : the journal of the British Epilepsy Association
April/7/2021
Abstract
Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.
Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".
Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.
Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
Keywords: EEG; Electro-clinical phenotype; Epilepsy; MEF2C, ADGRV1; Seizures; Therapy.
Publication
Journal: Molecular genetics & genomic medicine
November/6/2020
Abstract
Background: DYRK1A-Related Intellectual Disability Syndrome is a rare autosomal dominant condition characterized by intellectual disability, speech and language delays, microcephaly, facial dysmorphism, and feeding difficulties. Affected individuals represent simplex cases that result from de novo heterozygous pathogenic variants in DYRK1A (OMIM 614104), or chromosomal structural rearrangements involving the DYRK1A locus. Due to the rarity of DYRK1A-Related Intellectual Disability Syndrome, the spectrum of symptoms associated with this disease has not been completely defined.
Methods and results: We present two unrelated cases of DYRK1A-Related Intellectual Disability Syndrome resulting from variants in DYRK1A. Both probands presented to the National Institutes of Health (NIH) with multiple dysmorphic facial features, primary microcephaly, absent or minimal speech, feeding difficulties, and cognitive impairment; features that have been previously reported in individuals with DYRK1A. During NIH evaluation, additional features of enlarged cerebral subarachnoid spaces, retinal vascular tortuosity, and bilateral anomalous large optic discs with increased cup-to-disc ratio were identified in the first proband and multiple ophthalmologic abnormalities and sensorineural hearing loss were identified in the second proband.
Conclusion: We recommend that the workup of future of patients include a comprehensive eye exam. Early establishment of physical, occupational, and speech therapy may help in the management of ataxia, hypertonia, and speech impairments common in these patients.
Keywords: DYRK1A; Down syndrome; autosomal dominant mental retardation 7; feeding difficulties; microcephaly.
Publication
Journal: Hormones
April/19/2021
Abstract
Introduction: The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway.
Case reports and review: We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included.
Conclusions: PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.
Keywords: Hypoglycemia; Macrocephaly; Overgrowth; PI3K/AKT/mTOR signaling pathway; Review.
Publication
Journal: Brain and Development
June/6/2021
Abstract
Background: The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot-Marie-Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria.
Case reports: Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic-clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2.
Conclusions: DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.
Keywords: Dynein cytoplasmic 1 heavy chain 1 (DYNC1H1); Epilepsy; Lissencephaly; Malformations of cortical development (MCD); Pachygyria.
Publication
Journal: Chinese Journal of Medical Genetics
March/21/2021
Abstract
Objective: To explore the genetic basis for a child with mental and motor retardation, language impairment, facial dysmorphism and epilepsy.
Methods: Whole exome sequencing was carried out to detect pathogenic variant in the proband, and candidate variant was selected based on his phenotype. Sanger sequencing was used to verify the variant in the proband, his parents and other family members.
Results: The proband was found to carry a frameshifting mutation of MBD5 gene, namely c.2217delT (p.F739Lfs*6), which was inherited from his mother and unreported previously. Sanger sequencing confirmed that his brother carried the same mutation with a similar phenotype. His mother also had poor language expression when she was young, in addition with poor academic performance, though she could do some housework and had no history of convulsion.
Conclusion: A novel pathogenic variant of the MBD5 gene was discovered, which has enriched the mutational spectrum of the MBD5 gene. Above discovery has enabled genetic counseling and prenatal diagnosis for the family.