Bingbing Wu

A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

BackgroundAutistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism.Case presentationHere, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 – 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy.ConclusionsTo our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.

Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development

Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development. Importantly, two autism-associated truncations, R205X and E239X, were shown to be Dyrk1a loss-of-function mutants. Studies of the truncated Dyrk1a mutants may provide new insights into the role of Dyrk1a in brain development, as well as the role of Dyrk1a loss of function in the pathophysiology of autism.

Data on mutations and Clinical features in SCN1A or SCN2A gene

Mutations in SCN1A and SCN2A are associated with a wide spectrum of epilepsy related disorders in human. This dataset presented variants and clinical features of SCN1A and SCN2A genes. A total of 48 cases were presented, including 33 SCN1A mutations and 14 SCN2A mutations. While 22 mutations were novel in SCN1A and 11 were novel in SCN2A. The clinical features were included of gender, birth history, family history, seizure onset age, seizure types, frequency of seizures, initial and follow-up EEGs, brain MRI findings, antiepileptic drugs, prognosis and developmental data. The data can provide insights on novel mutations and different phenotypes of SCN1A and SCN2A.

Association between SCN1A and SCN2A mutations and clinical/EEG features in Chinese patients from epilepsy or severe seizures

BACKGROUND We investigated the association between SCN1A and SCN2A mutations and clinical phenotype and electroencephalography (EEG) features. METHODS In this study, 48 patients suffered from epilepsy or severe seizures with SCN1A and SCN2A mutations were recruited. Medical data and molecular diagnosis were analyzed. RESULTS A total of 47 mutations were identified, including 33 novel mutations. The onset of most epilepsy caused by SCN1A mutations (1-6 m) was later than that of SCN2A mutations (neonatal). SCN1A mutations included truncating mutations and missense mutations occurred in the crucial region were associated with more severe phenotypes and developmental delay (85.7%, P = 0.020). De novo mutations or truncating mutations of SCN2A mutations are mainly associated with severe phenotypes. The proportion of initial abnormal EEG of SCN2A mutation was higher than that of SCN1A mutation (54.2%, 100%). Patients with SCN1A mutations showed more focal epileptiform discharges (69.2%), while patients with SCN2A mutations had more multifocal epileptiform discharges (53.8%). Sodium channel blockers were less effective for patients with SCN1A mutations and SCN2A mutations with early seizures onset. CONCLUSIONS Our study expanded the mutation spectrum of the SCN1A and SCN2A, and led to a better understanding of the similarities and difference in the genetic and clinical features between the two genes.

Role of PUF60 gene in Verheij syndrome: a case report of the first Chinese Han patient with a de novo pathogenic variant and review of the literature

BackgroundVerheij syndrome is a rare microdeletion syndrome of chromosome 8q24.3 that harbors PUF60, SCRIB, and NRBP2 genes. Subsequently, loss of function mutations in PUF60 have been found in children with clinical features significantly overlapping with Verheij.Case presentationHere we present the first Chinese Han patient with a de novo nonsense variant (c.1357C > T, p.Gln453*) in PUF60 by clinical whole exome sequencing. The 5-year-old boy presents with dysmorphic facial features, intellectual disability, and growth retardation but without apparent cardiac, renal, ocular, and spinal anomalies.ConclusionsOur finding contributes to the understanding of the genotype and phenotype in PUF60 related disorder.

First reported Chinese case of guanidinoacetate methyltransferase deficiency in a 4-year-old child

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare inherited disorder characterized by creatine (Cr) depletion and guanidinoacetate (GAA) accumulation in body fluids. We report the first identified Chinese case, diagnosed in a 4-year-old girl with onset of global developmental. Low Cr and high GAA levels were detected in her serum and urine, and low Cr level in her brain. Compound heterozygous variants in GAMT gene were found, including a previously reported variant at c.491dupG which was inherited from her mother and a novel variant at c.564G>T, which was inherited from her father. The Cr and GAA levels returned back to normal after 3 months of treatment. After one year of treatment, the patient stopped taking antiepileptic drugs and her electroencephalogram (EEG) was also back to normal. The girl was followed up for five years and exhibited good results beyond our expectation. The results have shown that protein restriction with high-dose ornithine and creatine supplements have strong therapeutic potential for our patient.