De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review.

PURPOSE: PHF21A has been associated with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS). Here, we report a new patient with IDDBCS and review previously reported patients. METHODS: We reviewed the phenotypic and genetic spectrum of the newly diagnosed patient and previously reported patients with IDDBCS. RESULTS: Among 12 patients (11 whose cases were previously reported and the patient whose case we report here), all patients (100%) had intellectual disability (ID) and motor development delay. Three of 8 patients (37.5%) for whom information on cognition was available had severe ID; ID was moderate in two patients (25%) and mild in three patients (37.5%). Seven of the 12 patients (58.33%) had an epileptic phenotype, and the majority (5/7, 71.42%) of affected individuals developed developmental and epileptic encephalopathy (DEE). Of the 5 patients with DEE, three developed infantile epileptic spasm syndrome (IESS). The seizures of 2 patients (2/5, 40%) were controlled by antiseizure medications. Overgrowth, ADHD, hypotonia, ASD, and sleep disorders were observed in 100%, 77.78%, 70%, 50%, and 33.33% of patients, respectively. All of the variants (100%) were de novo heterozygous variants. Three of the 12 patients (25%) had the same variant (p.Arg580*). The most common types of variants were frameshift variants (7/12, 58.33%), followed by nonsense variants (4/12, 33.33%) and missense variants (1/12, 8.33%). Genotype-phenotype relationships for IDDBCS were uncertain, as phenotypic variability was observed among patients with the same variant (p.Arg580*). The patient whose case we report here had a novel PHF21A gene variant (p.Gln97fs*20), which caused neurodevelopmental delay, macrocephaly, and IESS. CONCLUSION: The core phenotypes of IDDBCS include neurodevelopmental delay (intellectual disability and impaired motor skills), craniofacial abnormalities, and overgrowth. ADHD, hypotonia, epilepsy, ASD, and sleep disorders are common symptoms of IDDBCS. Notably, DEE is the dominant phenotype of epilepsy, especially IESS. PHF21A may be a candidate gene for DEE. De novo variants are the main mode of inheritance. The most common types of variants are frameshift variants, and the variant p.Arg580* in PHF21A is located at a mutation hot spot.

Clinical application of whole exome sequencing technology in small-for-gestational-age children.

AIM: To apply whole exome sequencing (WES) for molecular diagnosis of small-for-gestational-age (SGA) children. METHODS: We retrospectively analyzed the data of 60 SGA children in our hospital, and performed developmental assessment, laboratory tests, imaging tests, and whole exome sequencing (WES), which were combined with clinical phenotypes to clarify the pathogenicity of the variant genes in the children. RESULTS: Sixty SGA children were tested, and pathogenic SGA was detected at relatively high frequencies on chromosomes 7, 8, and 22. Of these, karyotype analysis clearly suggested developmental disorders in 4 patients. Also, a case of Wiedemann-Steiner syndrome due to a de novo nonsense variant in the KMT2A gene was detected. CONCLUSIONS: The use of WES testing technology to increase the diagnosis rate of children with special SGA is conducive to the correct diagnosis and treatment of such children.

Potential Cross Talk between Autism Risk Genes and Neurovascular Molecules: A Pilot Study on Impact of Blood Brain Barrier Integrity.

Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was queried for individuals with a copy number variation (CNV) on microarray, Vineland, and Parent Concern Questionnaire scores. Pathway analyses of genes from pathogenic CNVs yielded 659 genes whose protein-protein interactions and mRNA expression mapped 121 genes with maximal antenatal expression in 12 brain regions. A Research Domain Criteria (RDoC)-derived neural circuits map revealed significant differences in anxiety, motor, and activities of daily living skills scores between altered CNV genes and normal microarrays subjects, involving Positive Valence (reward), Cognition (IQ), and Social Processes. Vascular signaling was identified as a biological process that may influence these neural circuits. Neuroinflammation, microglial activation, iNOS and 3-nitrotyrosine increase in the brain of Semaphorin 3F- Neuropilin 2 (Sema 3F-NRP2) KO, an ASD mouse model, agree with previous reports in the brain of ASD individuals. Signs of platelet deposition, activation, release of serotonin, and albumin leakage in ASD-relevant brain regions suggest possible blood brain barrier (BBB) deficits. Disruption of neurovascular signaling and BBB with neuroinflammation may mediate causative pathophysiology in some ASD subgroups. Although preliminary, these data demonstrate the potential for developing novel therapeutic strategies based on clinically derived data, genomics, cognitive neuroscience, and basic neuroscience methods.

Structural and Functional Characterization of Gray Matter Alterations in Female Patients With Neuropsychiatric Systemic Lupus.

Objective: To investigate morphological and functional alterations within gray matter (GM) in female patients with neuropsychiatric systemic lupus (NPSLE) and to explore their clinical significance. Methods: 54 female patients with SLE (30 NPSLE and 24 non-NPSLE) and 32 matched healthy controls were recruited. All subjects received a quantitative MRI scan (FLAIR, 3DT1, resting-state functional MRI). GM volume (GMV), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and degree of centrality (DC) were obtained. Between-group comparison, clinical correlation, and discrimination of NPSLE from non-NPSLE were achieved by voxel-based analysis, cerebellar seed-based functional connectivity analysis, regression analysis, and support vector machine (SVM), respectively. Results: Patients with NPSLE showed overt subcortical GM atrophy without significantly abnormal brain functions in the same region compared with controls. The dysfunction within the left superior temporal gyri (L-STG) was found precede the GM volumetric loss. The function of the nodes in default mode network (DMN) and salience network (SN) were weakened in NPSLE patients compared to controls. The function of the cerebellar posterior lobes was significantly activated in non-NPSLE patients but attenuated along with GM atrophy and presented higher connectivity with L-STG and DMN in NPSLE patients, while the variation of the functional activities in the sensorimotor network (SMN) was the opposite. These structural and functional alterations were mainly correlated with disease burden and anti-phospholipid antibodies (aPLs) (r ranges from -1.53 to 1.29). The ReHos in the bilateral cerebellar posterior lobes showed high discriminative power in identifying patients with NPSLE with accuracy of 87%. Conclusion: Patients with NPSLE exhibit both structural and functional alterations in the GM of the brain, which especially involved the deep GM, the cognitive, and sensorimotor regions, reflecting a reorganization to compensate for the disease damage to the brain which was attenuated along with pathologic burden and cerebral vascular risk factors. The GM within the left temporal lobe may be one of the direct targets of lupus-related inflammatory attack. The function of the cerebellar posterior lobes might play an essential role in compensating for cortical functional disturbances and may contribute to identifying patients with suspected NPSLE in clinical practice.

Different patterns of cerebral perfusion in SLE patients with and without neuropsychiatric manifestations.

To investigate brain perfusion patterns in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE and non-NPSLE, respectively) and to identify biomarkers for the diagnosis of NPSLE using noninvasive three-dimensional (3D) arterial spin labeling (ASL). Thirty-one NPSLE and 24 non-NPSLE patients and 32 age- and sex-matched normal controls (NCs) were recruited. Three-dimensional ASL-MRI was applied to quantify cerebral perfusion. Whole brain, gray (GM) and white matter (WM), and voxel-based analysis (VBA) were performed to explore perfusion characteristics. Correlation analysis was performed to find the relationship between the perfusion measures, lesion volumes, and clinical variables. Receiver operating characteristic (ROC) analysis and support vector machine (SVM) classification were applied to differentiate NPSLE patients from non-NPSLE patients and healthy controls. Compared to NCs, NPSLE patients showed increased cerebral blood flow (CBF) within WM but decreased CBF within GM, while non-NPSLE patients showed increased CBF within both GM and WM. Compared to non-NPSLE patients, NPSLE patients showed significantly reduced CBF in the frontal gyrus, cerebellum, and corpus callosum. CBF within several brain regions such as cingulate and corpus callosum showed significant correlations with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index scores. ROC analysis showed moderate performance in distinguishing NPSLE from non-NPSLE patients with AUCs > 0.7, while SVM analysis demonstrated that CBF within the corpus callosum achieved an accuracy of 83.6% in distinguishing NPSLE from non-NPSLE patients. Different brain perfusion patterns were observed between NPSLE and non-NPSLE patients. CBF measured by noninvasive 3D ASL could be a useful biomarker for the diagnosis and disease monitoring of NPSLE and non-NPSLE patients.

Radiomics in multiple sclerosis and neuromyelitis optica spectrum disorder.

OBJECTIVE: To develop and validate an individual radiomics nomogram for differential diagnosis between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). METHODS: We retrospectively collected 67 MS and 68 NMOSD with spinal cord lesions as a primary cohort and prospectively recruited 28 MS and 26 NMOSD patients as a validation cohort. Radiomic features were extracted from the spinal cord lesions. A prediction model for differentiating MS and NMOSD was built by combining the radiomic features with several clinical and routine MRI measurements. The performance of the model was assessed with respect to its calibration plot and clinical discrimination in the primary and validation cohorts. RESULTS: Nine radiomics features extracted from an initial set of 485, predominantly reflecting lesion heterogeneity, combined with lesion length, patient sex, and EDSS, were selected to build the model for differentiating MS and NMOSD. The areas under the ROC curves (AUC) for differentiating the two diseases were 0.8808 and 0.7115, for the primary and validation cohort, respectively. This model demonstrated good calibration (C-index was 0.906 and 0.802 in primary and validation cohort). CONCLUSIONS: A validated nomogram that incorporates the radiomic signature of spinal cord lesions, as well as cord lesion length, sex, and EDSS score, can usefully differentiate MS and NMOSD. KEY POINTS: • Radiomic features of spinal cord lesions in MS and NMOSD were different. • Radiomic signatures can capture pathological alterations and help differentiate MS and NMOSD.