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1.
Am J Hum Genet ; 105(5): 1048-1056, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31668703

RESUMO

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

2.
Top Magn Reson Imaging ; 28(5): 245-254, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31592991

RESUMO

Fetal magnetic resonance imaging (MRI) has been gaining increasing interest in both clinical radiology and research. Echoplanar imaging (EPI) offers a unique potential, as it can be used to acquire images very fast. It can be used to freeze motion, or to get multiple images with various contrast mechanisms that allow studying the microstructure and function of the fetal brain and body organs. In this article, we discuss the current clinical and research applications of fetal EPI. This includes T2*-weighted imaging to better identify blood products and vessels, using diffusion-weighted MRI to investigate connections of the developing brain and using functional MRI (fMRI) to identify the functional networks of the developing brain. EPI can also be used as an alternative structural sequence when banding or standing wave artifacts adversely affect the mainstream sequences used routinely in structural fetal MRI. We also discuss the challenges with EPI acquisitions, and potential solutions. As EPI acquisitions are inherently sensitive to susceptibility artifacts, geometric distortions limit the use of high-resolution EPI acquisitions. Also, interslice motion and transmit and receive field inhomogeneities may create significant artifacts in fetal EPI. We conclude by discussing promising research directions to overcome these challenges to improve the use of EPI in clinical and research applications.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31387860

RESUMO

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in VAC14, and the clinical phenotype is consistent with the recently described VAC14-related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054). However, the phenotype includes a distinct clinical presentation of retinitis pigmentosa (RP), which has not previously been reported in association with VAC14 mutations. Brain magnetic resonance imaging (MRI) revealed abnormal magnetic susceptibility in the globus pallidus, which can be seen in neurodegeneration with brain iron accumulation (NBIA). RP is a group of inherited retinal diseases with phenotypic/genetic heterogeneity, and the pathophysiologic basis of RP is not completely understood but is thought to be due to a primary retinal photoreceptor cell degenerative process. Most cases of RP are seen in isolation (non-syndromic); this is a report of RP in two siblings with VAC14-associated syndrome, and it is suggested that a connection between RP and VAC14-associated syndrome should be explored in future studies.

4.
Epilepsia ; 60(3): 406-418, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30682224

RESUMO

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

5.
Neuroimage ; 185: 593-608, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30172006

RESUMO

Altered structural fetal brain development has been linked to neuro-developmental disorders. These structural alterations can be potentially detected in utero using diffusion tensor imaging (DTI). However, acquisition and reconstruction of in utero fetal brain DTI remains challenging. Until now, motion-robust DTI methods have been employed for reconstruction of in utero fetal DTIs. However, due to the unconstrained fetal motion and permissible in utero acquisition times, these methods yielded limited success and have typically resulted in noisy DTIs. Consequently, atlases and methods that could enable groupwise studies, multi-modality imaging, and computer-aided diagnosis from in utero DTIs have not yet been developed. This paper presents the first DTI atlas of the fetal brain computed from in utero diffusion-weighted images. For this purpose an algorithm for computing an unbiased spatiotemporal DTI atlas, which integrates kernel-regression in age with a diffeomorphic tensor-to-tensor registration of motion-corrected and reconstructed individual fetal brain DTIs, was developed. Our new algorithm was applied to a set of 67 fetal DTI scans acquired from healthy fetuses each scanned at a gestational age between 21 and 39 weeks. The neurodevelopmental trends in the fetal brain, characterized by the atlas, were qualitatively and quantitatively compared with the observations reported in prior ex vivo and in utero studies, and with results from imaging gestational-age equivalent preterm infants. Our major findings revealed early presence of limbic fiber bundles, followed by the appearance and maturation of projection pathways (characterized by an age related increase in FA) during late 2nd and early 3rd trimesters. During the 3rd trimester association fiber bundles become evident. In parallel with the appearance and maturation of fiber bundles, from 21 to 39 gestational weeks gradual disappearance of the radial coherence of the telencephalic wall was qualitatively identified. These results and analyses show that our DTI atlas of the fetal brain is useful for reliable detection of major neuronal fiber bundle pathways and for characterization of the fetal brain reorganization that occurs in utero. The atlas can also serve as a useful resource for detection of normal and abnormal fetal brain development in utero.


Assuntos
Algoritmos , Atlas como Assunto , Encéfalo/embriologia , Desenvolvimento Fetal , Neurogênese , Imagem de Tensor de Difusão , Feminino , Feto , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino
6.
Neuroimage ; 188: 473-482, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30553042

RESUMO

Accurate parcellation and labeling of primary cortical sulci in the human fetal brain is useful for regional analysis of brain development. However, human fetal brains show large spatio-temporal changes in brain size, cortical folding patterns, and relative position/size of cortical regions, making accurate automatic sulcal labeling challenging. Here, we introduce a novel sulcal labeling method for the fetal brain using spatio-temporal gyrification information from multiple fetal templates. First, spatial probability maps of primary sulci are generated on the templates from 23 to 33 gestational weeks and registered to an individual brain. Second, temporal weights, which determine the level of contribution to the labeling for each template, are defined by similarity of gyrification between the individual and the template brains. We combine the weighted sulcal probability maps from the multiple templates and adopt sulcal basin-wise approach to assign sulcal labels to each basin. Our labeling method was applied to 25 fetuses (22.9-29.6 gestational weeks), and the labeling accuracy was compared to manually assigned sulcal labels using the Dice coefficient. Moreover, our multi-template basin-wise approach was compared to a single-template approach, which does not consider the temporal dynamics of gyrification, and a fully-vertex-wise approach. The mean accuracy of our approach was 0.958 across subjects, significantly higher than the accuracies of the other approaches. This novel approach shows highly accurate sulcal labeling and provides a reliable means to examine characteristics of cortical regions in the fetal brain.

7.
J Natl Compr Canc Netw ; 16(11): 1321-1328, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30442733

RESUMO

Background: Surveillance colonoscopy is required in patients with polyps due to an elevated colorectal cancer (CRC) risk; however, studies suggest substantial overuse and underuse of surveillance colonoscopy. The goal of this study was to characterize guideline adherence of surveillance recommendations after implementation of an electronic medical record (EMR)-based Colonoscopy Pathology Reporting and Clinical Decision Support System (CoRS). Methods: We performed a retrospective cohort study of patients who underwent colonoscopy with polypectomy at a safety-net healthcare system before (n=1,822) and after (n=1,320) implementation of CoRS in December 2013. Recommendations were classified as guideline-adherent or nonadherent according to the US Multi-Society Task Force on CRC. We defined surveillance recommendations shorter and longer than guideline recommendations as potential overuse and underuse, respectively. We used multivariable generalized linear mixed models to identify correlates of guideline-adherent recommendations. Results: The proportion of guideline-adherent surveillance recommendations was significantly higher post-CoRS than pre-CoRS (84.6% vs 77.4%; P<.001), with fewer recommendations for potential overuse and underuse. In the post-CoRS period, CoRS was used for 89.8% of cases and, compared with cases for which it was not used, was associated with a higher proportion of guideline-adherent recommendations (87.0% vs 63.4%; RR, 1.34; 95% CI, 1.23-1.42). In multivariable analysis, surveillance recommendations were also more likely to be guideline-adherent in patients with adenomas but less likely among those with fair bowel preparation and those with family history of CRC. Of 203 nonadherent recommendations, 70.4% were considered potential overuse, 20.2% potential underuse, and 9.4% were not provided surveillance recommendations. Conclusions: An EMR-based CoRS was widely used and significantly improved guideline adherence of surveillance recommendations.

8.
PLoS One ; 13(10): e0206365, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30359435

RESUMO

Human Immunodeficiency Virus-1 (HIV-1) entry is dependent on the envelope glycoprotein (Env) that is present on the virion and facilitates fusion between the envelope and the cellular membrane. The protein consists of two subunits, gp120 and gp41, with the former required for binding the CD4 receptor and either the CXCR4 or CCR5 coreceptor, and the latter for mediating fusion. The requirement of fusion for infection has made Env an attractive target for HIV therapy development and led to the FDA approval of enfuvirtide, a fusion inhibitor. Continued development of entry inhibitors is warranted because enfuvirtide resistant HIV-1 strains have emerged. In this study, a novel HIV-1 fusion assay was validated using neutralizing antibodies and then used to investigate the mechanism of action of eCD4-Igmim2, an HIV-1 inhibitor proposed to cooperatively bind the CD4 binding site and the sulfotyrosine-binding pocket of gp120. Greater reduction in fusion levels was observed with eCD4-Igmim2 in the fusion assay than all of the gp120 antibodies evaluated. Lab adapted isolates, HIV-1HXB2 and HIV-1YU2, were sensitive to eCD4-Igmim2 in the fusion assay, while primary isolates, HIV-1BG505 and HIV-1ZM651 were resistant. These results correlated with greater IC50 values for primary isolates compared to the lab adapted isolates observed in a virus neutralization assay. Analysis of gp120 models identified differences in the V1 and V2 domains that are associated with eCD4-Igmim2 sensitivity. This study highlights the use of a fusion assay to identify key areas for improving the potency of eCD4-Igmim2.

9.
Plast Reconstr Surg ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30325899

RESUMO

BACKGROUND: Endoscopic suturectomy and helmeting represents a successful first-line surgical treatment for bilateral coronal craniosynostosis. Its effect on cranial morphology has not been previously described. METHODS: Patients were identified who had bilateral coronal craniosynostosis treated with endoscopic suturectomy and postoperative helmeting at Boston Children's Hospital between 2005 and 2013 and who received pre- and post-operative CT scans. Two normative patient populations were identified from our trauma registry with CT scans completed at the same age as our pre- and post-treatment scans. Craniometric indices were utilized to quantify the effect of treatment. RESULTS: Twenty-seven patients were identified who underwent bilateral coronal suturectomy. Twelve patients had preoperative and postoperative CT studies. Eight patients (66.7%) were syndromic. The average ages for preoperative and postoperative CT scan was 1.1 months (0.03-2.6) and 19.6 months (10.8-37.5). Thirteen patients with an average age of 1.1 months (0.5-1.6) were identified as a preoperative control group. Fourteen patients with an average age of 18.5 months (15.5-22.9) were identified as a postoperative control group. The anterior cranial height (ACH) stabilized with treatment and the anterior cranial base length increased (ACBL). The ACH:ACBL ratio significantly decreased with treatment (p=0.128). Frontal bossing normalized with endoscopic suturectomy (CS vs control; pre-op: p=0.001, post-op (p=0.8). Cephalic indices also normalized with treatment (CS vs control; pre-op: p=0.02, post-op, p=0.13). No cases of hydrocephalus were observed. CONCLUSION: Endoscopic suturectomy and helmeting improves anterior turricephaly and corrects frontal bossing and brachycephaly in patients with bilateral coronal craniosynostosis.

11.
Cell Rep ; 24(4): 973-986.e8, 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30044992

RESUMO

Endosomal sorting complex required for transport (ESCRT) complex proteins regulate biogenesis and release of extracellular vesicles (EVs), which enable cell-to-cell communication in the nervous system essential for development and adult function. We recently showed human loss-of-function (LOF) mutations in ESCRT-III member CHMP1A cause autosomal recessive microcephaly with pontocerebellar hypoplasia, but its mechanism was unclear. Here, we show Chmp1a is required for progenitor proliferation in mouse cortex and cerebellum and progenitor maintenance in human cerebral organoids. In Chmp1a null mice, this defect is associated with impaired sonic hedgehog (Shh) secretion and intraluminal vesicle (ILV) formation in multivesicular bodies (MVBs). Furthermore, we show CHMP1A is important for release of an EV subtype that contains AXL, RAB18, and TMED10 (ART) and SHH. Our findings show CHMP1A loss impairs secretion of SHH on ART-EVs, providing molecular mechanistic insights into the role of ESCRT proteins and EVs in the brain.

12.
Mol Genet Metab ; 125(1-2): 118-126, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30031689

RESUMO

Folate metabolism in the brain is critically important and serves a number of vital roles in nucleotide synthesis, single carbon metabolism/methylation, amino acid metabolism, and mitochondrial translation. Genetic defects in almost every enzyme of folate metabolism have been reported to date, and most have neurological sequelae. We report 2 patients presenting with a neurometabolic disorder associated with biallelic variants in the MTHFS gene, encoding 5,10-methenyltetrahydrofolate synthetase. Both patients presented with microcephaly, short stature, severe global developmental delay, progressive spasticity, epilepsy, and cerebral hypomyelination. Baseline CSF 5-methyltetrahydrolate (5-MTHF) levels were in the low-normal range. The first patient was treated with folinic acid, which resulted in worsening cerebral folate deficiency. Treatment in this patient with a combination of oral L-5-methyltetrahydrofolate and intramuscular methylcobalamin was able to increase CSF 5-MTHF levels, was well tolerated over a 4 month period, and resulted in subjective mild improvements in functioning. Measurement of MTHFS enzyme activity in fibroblasts confirmed reduced activity. The direct substrate of the MTHFS reaction, 5-formyl-THF, was elevated 30-fold in patient fibroblasts compared to control, supporting the hypothesis that the pathophysiology of this disorder is a manifestation of toxicity from this metabolite.

13.
Ann Otol Rhinol Laryngol ; 127(10): 694-697, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30032646

RESUMO

OBJECTIVES: Vestibular schwannomas, also known as acoustic neuromas, are slow-growing tumors that may lead to asymmetric hearing loss, unilateral tinnitus, and vertigo. Population-based data are lacking regarding the incidence of vestibular schwannoma in Asian populations. The aim of this study was to investigate the incidence of vestibular schwannoma in Taiwan using data from a population-based health claim database. SUBJECTS AND METHODS: Patients aged 20 years and over with incident cases of vestibular schwannoma between January 1, 2001, and December 31, 2012, were identified from the Longitudinal Health Insurance Database 2000 of the National Health Insurance Research Database (NHIRD), Taiwan, based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 225.1. Only those patients who had received a magnetic resonance imaging scan prior to the diagnosis of vestibular schwannoma were considered as definitive cases. RESULTS: 206 cases of vestibular schwannoma were identified during the interval 2001 to 2012. The overall annual incidence was 2.66 per 100 000 persons (95% confidence interval, 2.32-3.05). The annual incidence rate varied throughout the study period, ranging from 1.74 to 3.72 per 100 000 persons. The highest incidence rate of 4.86 per 100 000 persons was observed in the age group of 60 to 69 years. CONCLUSIONS: Based on data from the NHIRD in Taiwan for the years 2001 to 2012, the average annual incidence rate of vestibular schwannoma was found to be 2.66 per 100 000 persons.


Assuntos
Neuroma Acústico/epidemiologia , Vigilância da População , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroma Acústico/diagnóstico , Estudos Retrospectivos , Distribuição por Sexo , Taiwan/epidemiologia , Adulto Jovem
14.
Mol Genet Metab Rep ; 16: 23-29, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29922587

RESUMO

Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

15.
Ann Neurol ; 83(6): 1133-1146, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29679388

RESUMO

OBJECTIVE: Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including nonlesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS: We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS: We observed somatic variants in 5 cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3 of 18 individuals (17%) with NLFE, 1 female and 2 males, with variant allele frequencies (VAFs) in brain-derived DNA of 2 to 14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in 2 of the 3 NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of 2 males with intractable epilepsy, developmental delay, and magnetic resonance imaging suggesting FCD, with VAFs of 19 to 53%; Evidence for FCD was not observed in either brain tissue specimen. INTERPRETATION: We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies. Ann Neurol 2018.

16.
Cell ; 173(5): 1111-1122.e10, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29606355

RESUMO

The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High-resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease.

17.
Mol Genet Metab ; 124(2): 161-167, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29685658

RESUMO

Congenital disorders of manganese metabolism are rare occurrences in children, and medical management of these disorders is complex and challenging. Homozygous exonic mutations in the manganese transporter SLC39A14 have recently been associated with a pediatric-onset neurodegenerative disorder characterized by brain manganese accumulation and clinical signs of manganese neurotoxicity, including parkinsonism-dystonia. We performed whole exome sequencing on DNA samples from two unrelated female children from the United Arab Emirates with progressive movement disorder and brain mineralization, identified a novel homozygous intronic mutation in SLC39A14 in both children, and demonstrated that the mutation leads to aberrant splicing. Both children had consistently elevated serum manganese levels and were diagnosed with SLC39A14-associated manganism. Over a four-year period, we utilized a multidisciplinary management approach for Patient 1 combining decreased manganese dietary intake and chelation with symptomatic management of dystonia. Our treatment strategy appeared to slow disease progression, but did not lead to a cure or reversal of already established deficits. Clinicians should consider testing for noncoding mutations in the diagnosis of congenital disorders of manganese metabolism and utilizing multidisciplinary approaches in the management of these disorders.

20.
Am J Hum Genet ; 102(5): 995-1007, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656858

RESUMO

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.

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