Gene-Focused Networks Underlying Phenotypic Convergence in a Systematically Phenotyped Cohort With Heterogeneous Intellectual Disability.

The broad spectrum of intellectual disability (ID) patients' clinical manifestations, the heterogeneity of ID genetic variation, and the diversity of the phenotypic variation represent major challenges for ID diagnosis. By exploiting a manually curated systematic phenotyping cohort of 3803 patients harboring ID, we identified 704 pathogenic genes, 3848 pathogenic sites, and 2075 standard phenotypes for underlying molecular perturbations and their phenotypic impact. We found the positive correlation between the number of phenotypes and that of patients that revealed their extreme heterogeneities, and the relative contribution of multiple determinants to the heterogeneity of ID phenotypes. Nevertheless, despite the extreme heterogeneity in phenotypes, the ID genes had a specific bias of mutation types, and the top 44 genes that ranked by the number of patients accounted for 39.9% of total patients. More interesting, enriched co-occurrent phenotypes and co-occurrent phenotype networks for each gene had the potential for prioritizing ID genes, further exhibited the convergences of ID phenotypes. Then we established a predictor called IDpred using machine learning methods for ID pathogenic genes prediction. Using10-fold cross-validation, our evaluation shows remarkable AUC values for IDpred (auc = 0.978), demonstrating the robustness and reliability of our tool. Besides, we built the most comprehensive database of ID phenotyped cohort to date: IDminer http://218.4.234.74:3100/IDminer/, which included the curated ID data and integrated IDpred tool for both clinical and experimental researchers. The IDminer serves as an important resource and user-friendly interface to help researchers investigate ID data, and provide important implications for the diagnosis and pathogenesis of developmental disorders of cognition.

Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria.

BACKGROUND: L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare organic aciduria neurometabolic disease that is inherited as an autosomal recessive mode and have a variety of symptoms, such as psychomotor developmental retardation, epilepsy, cerebral symptoms as well as increased concentrations of 2-hydroxyglutarate (2-HG) in the plasma, urine and cerebrospinal fluid. The causative gene of L-2-HGA is L-2-hydroxyglutarate dehydrogenase gene (L2HGDH), which consists of 10 exons. CASE PRESENTATION: We presented a rare patient primary diagnosis of L-2-HGA based on the clinical symptoms, magnetic resonance imaging (MRI), and gas chromatography-mass spectrometry (GC-MS) results. Mutational analysis of the L2HGDH gene was performed on the L-2-HGA patient and his parents, which revealed two novel mutations in exon 3: a homozygous missense mutation (c.407 A > G, p.K136R) in both the maternal and paternal allele, and a heterozygous frameshift mutation [c.407 A > G, c.408 del G], (p.K136SfsX3) in the paternal allele. The mutation site p.K136R of the protein was located in the pocket of the FAD/NAD(P)-binding domain and predicted to be pathogenic. CONCLUSION: We predicted the homozygous missense mutation (c.407 A > G, p.K136R) was considered as the pathogenic mutation of the patient. The study highlights the power of pedigree analysis in order to interpret novel mutations.

[Detection of subtelomeric copy number variations in children with intellectual disability].

OBJECTIVE: To detect subtelomeric copy number variations in children with genetic intellectual disability (ID) using multiplex ligation-dependent probe amplification (MLPA), and to investigate the pathogenesis of genetic ID. METHODS: A total of 68 children with ID who had normal results of G-banding karyotype analysis were included in the study. Their subtelomeric copy number variations were detected using MLPA P036. RESULTS: Among the 68 children with ID, 7(10%) showed subtelomeric copy number variations, and all the variations were deletion mutations. Among them, 1 case carried 2 subtelomeric microdeletions, and 1 case carried 4 subtelomeric microdeletions. CONCLUSIONS: Subtelomeric copy number variations are important causes of genetic ID. MLPA can be used as an economic and effective method for investigating the pathogenesis of genetic ID.

[Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts].

The clinical data of a patient with megalencephalic leukoencephalopathy (MLC) with subcortical cysts and her parents were collected. MLC1 gene mutation was detected by polymerase chain reaction and direct DNA sequencing. The patient presented with motor developmental delay and giant skull, and brain magnetic resonance imaging showed diffuse white matter swelling accompanied by subcortical cysts in bilateral frontal and parietal lobes. Gene sequencing identified two heterozygous mutations of MLC1, including missense mutation in exon 3 (c.217G>A, p.Gly73Arg) and splice site mutation in intron 9 (c.772-1G>C in IVS9-1). The patient's parents both had heterozygous mutation c.772-1G>C in IVS9-1 with normal phenotype. It can be presumed that c.772-1G>C in IVS9-1 comes from the parents, and c.217G>A (p.Gly73Arg) is a de novo mutation.

Perinatal occipital lobe injury in children: analysis of twenty-one cases.

This study used magnetic resonance imaging to analyze causes and clinical courses of pediatric occipital lobe injury. Patients undergoing magnetic resonance imaging for suspected bilateral occipital lobe injury at our Neurodevelopmental Department between July 2007 and June 2011 were included. We evaluated magnetic resonance imaging characteristics, clinical courses, electroencephalogram monitoring, and Denver Development Screen Test scores. Twenty-one infants were examined. Of these, 10 had been born preterm. Thirteen patients demonstrated hypoglycemia. Perinatal period hypoglycemia comprised the most common cause (71.4%) of occipital brain injury. Visual abnormalities were evident in 18 patients. Seventeen (80.9%) patients manifested epilepsy. Infantile spasms were observed in 13 cases (76.5%). According to Denver Development Screen Test assessment, 17 patients demonstrated delayed motor development. Motor function and language improved in 10 patients after effective control of their seizures. Hypoglycemia constitutes the most common cause of occipital injury in infants. Visual impairment, startle episodes, infantile spasms, and motor developmental delay comprise the most common complications, whereas language function is usually spared.

[Clinical features and SCN1A gene mutation analysis of severe myoclonic epilepsy of infancy].

OBJECTIVE: Severe myoclonic epilepsy of infancy (SMEI), or Dravet syndrome, is a severe epileptic encephalopathy. This study aimed to investigate the clinical features and genetic diagnosis of SMEI. METHODS: The electroclinical data and the mutation of SCN1A gene in 13 children with SMEI were analyzed. RESULTS: Of the 13 children, 10 were males and 3 were females. Eight of them had family history of febrile seizures. The average age of seizure onset was 5.6 months, with a range of 2 to 9 months. The initial seizure was a febrile seizure in 9 patients (69%). Generalized or hemiclonic seizures were often triggered by fever. Eight patients had a history of febrile status. Afebrile seizures occurred from 2 months to 21 months of age. All patients went on to develop multiple seizure types. Generalized tonic clonus seizures (GTCS) were found in 11, partial seizures in 12, atypical absence in 10. Myoclonic seizures were presented in all patients. Twelve patients had 3 or more seizure types. Seizures of all patients had a characteristic of temperature sensitivity. The precipitating factors included fever, hot bath and vaccination. Nine patients (69%) had a history of status epilepticus. Delay in mental development was present in 11 cases, ataxia in 5 and pyramidal sign in 2. EEG was normal in most patients in the first year of life, followed by generalized, focal and multifocal discharges. Brain MRI was abnormal in 2 cases. Seizures were not completely controlled in all patients. Carbamazepine and lamotrigine aggravated seizures in some patients. SCN1A gene mutation was found in 10 cases, including seven missense mutations, two nonsense mutations and one frame shift mutation. CONCLUSION: The clinical features of SMEI were seizure onset within one year of age, first event is often a febrile seizure; multiple seizure types and mental delay occurred after the second year of life; seizures have a characteristic of temperature sensitivity; EEG was normal in the first year of life, followed by generalized, focal or multifocal discharges; early diagnosis by testing SCN1A mutation guides selection of antiepileptic drugs.