WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.
We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).
We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.
Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

To study the burden of neurodevelopmental diseases (NDDs) via cost-of-illness analysis of Chinese patients with genetic diagnosis.
We recruited NDD patients (0-18 years old) with genetic diagnosis (GD) from September 1, 2020 to January 30, 2021. We gathered basic information on the details of diagnosis, as well as the direct medical cost, direct non-healthcare cost and indirect cost before and after receiving GD. We corrected the cost for time biases by calculating the cost per day for each patient.
For the 502 patients with NDDs, the mean age was 4.08 ± 3.47. The household income was 0.6 (0.4, 1.0) 10,000 CNY per-month on average. The direct medical cost, direct non-healthcare cost and indirect cost were 12.27 (7.36, 22.23) 10,000 CNY, 1.45 (0.73, 2.69)10,000 CNY and 14.14(4.80, 28.25) 10,000 CNY per patient, respectively. Every patient received 1.20 (0.34, 3.60) 10,000 CNY on average (15.91%) from insurance. The daily total cost after receiving GD were ~62.48% lower than those before GD (191.59 CNY vs. 71.45 CNY). The descend range of lab cost (95.77%, P < 0.05) was the largest, followed by drugs (91.39%, P < 0.05), hospitalization (90.85%, P < 0.05), and consultation (57.41%, P < 0.05). The cost of rehabilitation kept slightly increasing but there were no significant differences (P > 0.05). The daily direct medical cost of each patient fell by 75.26% (P < 0.05) from 311.79 CNY to 77.14 CNY when the diagnostic age was younger than 1, and declined by 49.30% (P < 0.05) and 8.97% (P > 0.05) when the diagnostic age was 1-3 and older than 3, respectively.
Early genetic diagnosis is crucial for to reducing the burden of disease because of the amount of money spent was lower when they are diagnosed at younger age. Patients with NDDs can incur a heavy economic burden, especially in rehabilitation cost and indirect cost, because the insurance coverage for patients is low, so it is urgent for governments to pay more attention to these issues.

Arboleda-Tham syndrome (OMIM#616268) is a newly named neurodevelopmental disorder, which is an autosomal dominant hereditary disease characterized by genetic variants. The clinical manifestations include global developmental delay, primary microcephaly, and craniofacial dysmorphism, as well as more varied features such as feeding difficulties, cardiac defects, and ocular anomalies. Currently, due to restricted knowledge of Arboleda-Tham syndrome and less specific pathological manifestations, it is difficult to diagnose at the early stages of the disease. Here, we present a case with obvious growth retardation and intellectual disability, accompanied by other manifestations including dysmorphic features of the ears, facial dysmorphism, right cryptorchidism, and inguinal hernia. Routine laboratory tests including blood-urine tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, echocardiography, automatic auditory brainstem responses, serum levels of calcium, phosphorus, vitamin D, creatine kinase (CK), and CK isoenzyme (CK-MB), and brain magnetic resonance imaging showed negative results. A de novo heterozygous variant in KAT6A, c.57delA (p.Val20*), was detected by trio-based whole exome sequencing and subsequent validation by Sanger sequencing in the patient, which was absent in both the parents. The patient received rehabilitation and nutritional intervention. The testis reduction and orchiopexy was scheduled when he was 1 year old. Our report extends the phenotype-genotype map of Arboleda-Tham syndrome, and also expands the mutant spectrum of the KAT6A gene. Moreover, this case emphasizes the timely conduction of whole exome sequencing for the early diagnosis of Arboleda-Tham syndrome, and spares patients from meaningless examinations and ineffective treatments.

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental disorders, including autistic disorder, Asperger\'s syndrome, pervasive developmental disorder and childhood disintegrative disorder. Mitochondria not only provide neurons with energy in the form of ATP to sustain neuron growth, proliferation and neurodevelopment, but also regulate neuron apoptosis, intracellular calcium ion (Ca2+) homeostasis, and reactive oxygen species (ROS) clearance. Due to their postmitotic state and high energy-demanded feature, neurons are particularly prone to mitophagy and mitochondrial disfunction. Mitophagy, a selective autophagy, is critical for sustaining mitochondrial turnover and quality control via eliminating unwanted and dysfunctional mitochondria in neurons. Dysfunctional mitochondria and dysregulated mitophagy have been closely associated with the onset of ASDs. In this review, we summarize the mechanism of mitophagy and its role in neurons, and the consequence of mitophagy dysfunction in ASDs. Deeper appreciation of the role of mitophagy in ASDs pathology is required for developing new therapeutic approaches.

Background: BCL11B encodes B-cell lymphoma/leukemia 11B, a transcription factor that participates in the differentiation and migration of neurons and lymphocyte cells. De novo mutations of BCL11B have been associated with neurodevelopmental disorder and immunodeficiency, such as immunodeficiency 49 (IMD49) and intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities (IDDSFTA). However, the pathogenesis of the neurodevelopmental disorder and T-cell deficiency is still mysterious. The strategy to distinguish these two diseases in detail is also unclear. Methods: A patient with unique clinical features was identified. Multiple examinations were applied for evaluation. Whole-exome sequencing (WES) and Sanger sequencing were also performed for the identification of the disease-causing mutation. Results: We reported a 17-month-old girl with intellectual disability, speech impairment, and delay in motor development. She presented with mild dysmorphic facial features and weak functional movement. MRI indicated the abnormal myelination of the white matter. Immunological analysis showed normal levels of RTEs and γδT cells but a deficiency of naive T cells. Genetic sequencing identified a de novo heterozygous frameshift mutation c.1192_1196delAGCCC in BCL11B. Conclusions: An IDDSFTA patient of East Asian origin was reported. The unreported neurological display, immunophenotype, and a novel disease-causing mutation of the patient extended the spectrum of clinical features and genotypes of IDDSFTA.

Neurodevelopmental diseases are a class of neurodevelopmental disorders characterized by cognitive impairment and behavioral abnormalities and are mainly manifested as developmental disorders of the brain and nervous system. The pathological mechanism is not fully understood and may be related to hereditary or environmental factors. The elevation of autophagy during neural development suggests that autophagy may be involved in the process of neurodevelopment. This chapter focuses on the important functions of autophagy in all aspects of neurodevelopment and the role and mechanism of autophagy in neurodevelopmental disorders, especially in autism spectrum disorder.

Processes associated with human brain development and function are exceedingly complex, limiting our capacity to investigate disease status and potential treatment strategies in vitro. Recent advancements in human cerebral organoid systems-which replicate early stage neural tube formation, neuroepithelium differentiation, and whole-brain regional differentiation-have allowed researchers to generate more accurate models of brain development and disease. The generation of region-specific cerebral organoids also allows for the direct investigation of the etiology and pathological processes associated with inherited and acquired brain diseases, drug discovery, and drug toxicity. In this review, we provide an overview of various neural differentiation technologies, as well as a critical analysis of their strengths and limitations. We primarily focus on the generation of three-dimensional brain organoid systems and their application in infectious disease modeling, high-throughput compound screening, and neurodevelopmental disease modeling.