Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

PURPOSE: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. METHODS: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. RESULTS: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. CONCLUSION: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.

Clinical and molecular characterization of a patient with mitochondrial Neurogastrointestinal Encephalomyopathy.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in TYMP gene, encoding nuclear thymidine phosphorylase (TP). MNGIE mainly presents with gastrointestinal symptoms and is mostly misdiagnosed in many patients as malabsorption syndrome, inflammatory bowel disease, anorexia nervosa, and intestinal pseudo-obstruction. Up to date, more than 80 pathogenic and likely pathogenic mutations associated with the disease have been reported in patients from a wide range of ethnicities. The objective of this study was to investigate the underlying genetic abnormalities in a 25-year-old woman affected with MNGIE. CASE PRESENTATION: The patient was a 25-year-old female referred to our center with the chief complaint of severe abdominal pain and diarrhea for 2 years that had worsened from 2 months prior to admission. The clinical and para-clinical findings were in favor of mitochondrial neurogastrointestinal encephalomyopathy syndrome. Subsequent genetic studies revealed a novel, private, homozygous nonsense mutation in TYMP gene (c. 1013 C > A, p.S338X). Sanger sequencing confirmed the new mutation in the proband. Multiple sequence alignment showed high conservation of amino acids of this protein across different species. CONCLUSION: The detected new nonsense mutation in the TYMP gene would be very important for genetic counseling and subsequent early diagnosis and initiation of proper therapy. This novel pathogenic variant would help us establish future genotype-phenotype correlations and identify different pathways related to this disorder.

Association between rs2303861 polymorphism in CD82 gene and non-alcoholic fatty liver disease: a preliminary case-control study.

AIM: To investigate the genetic factors involved in the development of non-alcoholic fatty liver disease (NAFLD) and its sequelae in a Middle Eastern population. METHODS: This genetic case-control association study, conducted in 2018, enrolled 30 patients with NAFLD and 30 control individuals matched for age, sex, and body mass index. After quality control measures, entire exonic regions of 3654 genes associated with human diseases were sequenced. Allelic association test and enrichment analysis of the significant genetic variants were performed. RESULTS: The association analysis was conducted on 27 NAFLD patients and 28 controls. When Bonferroni correction was applied, NAFLD was significantly associated with rs2303861, a variant located in the CD82 gene (P=2.49×10-7, adjusted P=0.0059). When we used Benjamini-Hochberg adjustment for correction, NAFLD was significantly associated with six more variants. Enrichment analysis of the genes corresponding to all the seven variants showed significant enrichment for miR-193b-5p (P=0.00004, adjusted P=0.00922). CONCLUSION: A variant on CD82 gene and a miR-193b expression dysregulation may have a role in the development and progression of NAFLD and its sequelae.

Genetic Testing in Various Neurodevelopmental Disorders Which Manifest as Cerebral Palsy: A Case Study From Iran.

Purpose: Cerebral palsy (CP) is a heterogeneous permanent disorder impacting movement and posture. Investigations aimed at diagnosing this disorder are expensive and time-consuming and can eventually inconclusive. This study aimed to determine the diagnostic yield of next generation sequencing in patients with atypical CP (ACP). Methods: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following conditions: severe intellectual disability, positive family history, brain imaging findings not typical for cerebral palsy, abnormal neurometabolic profile, intractable seizure, normal neuroimaging despite severe psychomotor disability, after pediatric neurologist assessment including neuroimaging and biochemical-metabolic study offered for genetic study. Results: Exome sequencing was done for 66 patients which revealed pathogenic, likely pathogenic, and variants of unknown significance in 36.2, 9, and 43.9%, respectively. We also found 10 new mutations and were able to suggest specific and personalized treatments for nine patients. We also found three different mutations with different phenotypical spectrum in one gene that have not been reported for cerebral palsy. Conclusion: An accurate history and physical examination and determination of patients with atypical cerebral palsy for doing exome sequencing result in improved genetic counseling and personalized management.