Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

Thigh MRI in antisynthetase syndrome, and comparisons with dermatomyositis and immune-mediated necrotizing myopathy.

OBJECTIVES: To evaluate MRI changes to define muscle-lesion specific patterns in patients with antisynthetase syndrome (ASS), and compare them with those in other common idiopathic inflammatory myopathy subtypes. METHODS: Qualitative and semi-quantitative thigh MRI evaluations were conducted in patients with ASS, DM and immune-mediated necrotizing myopathy (IMNM). RESULTS: This study included 51 patients with ASS, 56 with DM and 61 with IMNM. Thigh MRI revealed muscle oedema (62.7%), myofascial oedema (90.2%), subcutaneous-tissue oedema (60.8%) and fatty infiltration of muscles (68.6%) in patients with ASS. Compared with IMNM, ASS and DM were associated with more frequent adductor-muscle relative sparing (40.6% vs 3.6%, P<0.001, and 25.6% vs 3.6%, P<0.001) and subcutaneous-tissue oedema (60.8% vs 23.0%, P<0.001, and 57.1% vs 23.0%, P<0.001). Although ASS and DM exhibited similar oedema patterns, there were certain subtle differences between them. The ASS group was less frequently symmetric (60.6% vs 88.4%, P=0.005, and 60.6% vs 80.0%, P=0.048), but more frequently showed myofascial oedema of the tensor fasciae latae (80.4% vs 48.2%, P<0.001, and 80.4% vs 31.1%, P<0.001) than either the DM or IMNM groups. The receiver operating characteristic curve analysis showed an optimal combination of thigh MRI findings had an area under the curve with 0.893 for diagnosing ASS. CONCLUSION: Thigh MRI in ASS exhibited frequent myofascial oedema. ASS oedema patterns resembled those of DM more than those of IMNM. Bilateral asymmetry, adductor-muscle relative sparing and remarkable myofascial oedema of tensor fasciae latae were the most characteristic ASS imaging findings.

[Clinical and genetic analysis of three children with 22q13 deletion syndrome].

OBJECTIVE: To explore the clinical and genetic characteristics of three children with 22q13 deletion syndrome. METHODS: Clinical data were collected and copy number variations in the patients and their parents were detected by using array-based comparative genomic hybridization (aCGH) and copy number variation sequencing (CNV-seq). The DECIPHER, ClinGen, OMIM, PubMed and Gene Review databases were retrieved for pathogenicity analysis. RESULTS: The common phenotypes of the three children have included variable global developmental delay, among which speech delay was the most obvious. Patient 1 had abnormalities of corpus callosum shown by magnetic resonance imaging. Patient 2 had dental crowding, pale skin, thick palms, hypotonia, and other facial features. Patient 3 had the mildest symptoms including language dysfunction, which has caught up with the development and improved significantly. All of the three children had harbored de novo deletions of 22q13.33q13.33 region, which spanned 0.84 Mb, 8.70 Mb and 0.90 Mb and involved 37, 126, and 34 genes, respectively. CONCLUSION: Above finding has enriched the clinical and genetic characteristics of 22q13 deletion syndrome and laid a foundation for genetic counseling and prenatal diagnosis.

Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.

A deep learning model for diagnosing dystrophinopathies on thigh muscle MRI images.

BACKGROUND: Dystrophinopathies are the most common type of inherited muscular diseases. Muscle biopsy and genetic tests are effective to diagnose the disease but cost much more than primary hospitals can reach. The more available muscle MRI is promising but its diagnostic results highly depends on doctors' experiences. This study intends to explore a way of deploying a deep learning model for muscle MRI images to diagnose dystrophinopathies. METHODS: This study collected 2536 T1WI images from 432 cases who had been diagnosed by genetic analysis and/or muscle biopsy, including 148 cases with dystrophinopathies and 284 cases with other diseases. The data was randomly divided into three sets: the data from 233 cases were used to train the CNN model, the data from 97 cases for the validation experiments, and the data from 102 cases for the test experiments. We also validated our models expertise at diagnosing by comparing the model's results on the 102 cases with those of three skilled radiologists. RESULTS: The proposed model achieved 91% (95% CI: 0.88, 0.93) accuracy on the test set, higher than the best accuracy of 84% in radiologists. It also performed better than the skilled radiologists in sensitivity : sensitivities of the models and the doctors were 0.89 (95% CI: 0.85 0.93) versus 0.79 (95% CI:0.73, 0.84; p = 0.190). CONCLUSIONS: The deep model achieved excellent accuracy and sensitivity in identifying cases with dystrophinopathies. The comparable performance of the model and skilled radiologists demonstrates the potential application of the model in diagnosing dystrophinopathies through MRI images.

Comparison of the Efficacy and Safety of the American Thyroid Association Guidelines and American College of Radiology TI-RADS.

OBJECTIVE: To evaluate the 2015 American Thyroid Association (ATA) guidelines and 2017 American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) for their efficacy in predicting malignant thyroid nodules and safety in recommending fine needle aspiration (FNA). METHODS: We reviewed data of 970 thyroid nodules from 908 patients with core needle biopsy pathology. We calculated the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for each guideline to predict malignancies. We compared the areas under the curve and FNA recommendations between the 2 guidelines. RESULTS: According to the core needle biopsy pathology, 59.9% (581/970) of the thyroid nodules were malignant. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value was 68%, 91%, 33%, 67%, and 70%, respectively, for the ATA guidelines and 70%, 84%, 49%, 71%, and 68%, respectively, for the ACR TI-RADS. Areas under the curve (ATA: 0.71 vs ACR TI-RADS: 0.74; P = .054) were similar when predicting malignancies. For the 545 nodules with maximum diameter ≥1.0 cm, the ACR TI-RADS recommended FNA less often than the ATA guidelines (83.3% [454/545] vs 87.7% [478/545]; P = .01). For the 321 malignant nodules with maximum diameter ≥1.0 cm, the proportions of FNA recommendations were not significantly different (ACR TI-RADS: 90.7% [291/321] vs ATA: 92.5% [297/321]; P = .06). CONCLUSION: The 2015 ATA guidelines and 2017 ACR TI-RADS showed a similar ability in predicting malignancies. Reducing FNA recommendations by the ACR TI-RADS would not lead to a significant decrease in the FNA recommendations given for malignancies with maximum diameter ≥1.0 cm.

Phenotypic spectrum of patients with GABRB2 variants: from mild febrile seizures to severe epileptic encephalopathy.

AIM: To characterize the different phenotypes of GABRB2-related epilepsy and to establish a genotype-phenotype correlation. METHOD: We used next-generation sequencing to identify GABRB2 variants in 15 patients. RESULTS: Eleven GABRB2 variants were novel and 12 were de novo. The age at the onset of seizures ranged from 1 day to 26 months. Nine patients had multiple seizure types, including focal seizures, generalized tonic-clonic seizures, myoclonic seizures, epileptic spasms, and atonic seizures. Seizures were fever-sensitive in 13 out of the 15 patients. Eleven patients displayed developmental delay, while 11 had abnormal video electroencephalography. Abnormalities in the brain images included dysplasia of the frontal and temporal cortex, dysplasia of the corpus callosum, and delayed myelination in four patients. One patient was diagnosed with febrile seizures, three with febrile seizures plus, three with Dravet syndrome, three with West syndrome, one with Ohtahara syndrome, three with developmental delays and epilepsy, and one with non-specific early-onset epileptic encephalopathy. INTERPRETATION: The most common phenotypes of patients with GABRB2 variants include early onset of seizure and fever sensitivity. Febrile seizures and febrile seizures plus are new phenotypes of GABRB2 variants. The phenotypic spectrum of GABRB2 variants ranges from mild febrile seizures to severe epileptic encephalopathy.

Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene.

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.

FHL1-related clinical, muscle MRI and genetic features in six Chinese patients with reducing body myopathy.

Reducing body myopathy is a rare X-linked myopathy characterized by the presence of reducing bodies. The causative gene has been identified as FHL1. We presented with the clinical, muscle magnetic resonance imaging and genetic features of 6 unrelated Chinese patients with reducing body myopathy. We divided the patients into 2 groups according to their age at onset. In addition to limb muscle weakness, pronounced axial muscle involvement was a striking feature common to both groups. Muscle magnetic resonance imaging revealed fatty infiltration predominantly in the postero-medial muscles of the thigh and the soleus muscle of the calf, sparing the gluteus and sartorius muscles. Muscle pathology demonstrated the muscle fibres with reducing bodies distributed in small groups. Genetic analysis revealed FHL1 hemizygote variants in the 6 patients, including 4 novel and 2 reported variants. These variants were located in the LIM2 domain of FHL1 in 4 patients, but 2 located in the LIM4 domain. To the best of our knowledge, this is the first report of reducing body myopathy in the Chinese population. Our findings expand the genetic spectrum of reducing body myopathy.