Diagnostic yield of the chromosomal microarray analysis in turkish patients with unexplained development delay/intellectual disability(ID), autism spectrum disorders and/or multiple congenital anomalies and new clinical findings.

BACKGROUND: Chromosomal microarray analysis is an essential tool for copy number variants detection in patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The study aims to determine the clinical significance of chromosomal microarray analysis in this patient group. Another crucial aspect is the evaluation of copy number variants detected in terms of the diagnosis of patients. METHODS AND RESULTS: A Chromosomal microarray analysis was was conducted on a total of 1227 patients and phenotype-associated etiological diagnosis was established in 135 patients. Phenotype-associated copy number variants were detected in 11% of patients. Among these, 77 patients 77 (57%, 77/135) were diagnosed with well-recognized genetic syndromes and phenotype-associated copy number variants were found in 58 patients (42.9%, 58/135). The study was designed to collect data of patients in Kocaeli Derince Training and Research Hospital retrospectively. In our study, we examined 135 cases with clinically significant copy number variability among all patients. CONCLUSIONS: In this study, chromosomal microarray analysis revealed pathogenic de novo copy number variants with new clinical features. Chromosomal microarray analysis in the Turkish population has been reported in the largest patient cohort to date.

Genetic and phenotypic analysis of 225 Chinese children with developmental delay and/or intellectual disability using whole-exome sequencing.

Developmental delay (DD), or intellectual disability (ID) is a very large group of early onset disorders that affects 1-2% of children worldwide, which have diverse genetic causes that should be identified. Genetic studies can elucidate the pathogenesis underlying DD/ID. In this study, whole-exome sequencing (WES) was performed on 225 Chinese DD/ID children (208 cases were sequenced as proband-parent trio) who were classified into seven phenotype subgroups. The phenotype and genomic data of patients with DD/ID were further retrospectively analyzed. There were 96/225 (42.67%; 95% confidence interval [CI] 36.15-49.18%) patients were found to have causative single nucleotide variants (SNVs) and small insertions/deletions (Indels) associated with DD/ID based on WES data. The diagnostic yields among the seven subgroups ranged from 31.25 to 71.43%. Three specific clinical features, hearing loss, visual loss, and facial dysmorphism, can significantly increase the diagnostic yield of WES in patients with DD/ID (P = 0.005, P = 0.005, and P = 0.039, respectively). Of note, hearing loss (odds ratio [OR] = 1.86%; 95% CI = 1.00-3.46, P = 0.046) or abnormal brainstem auditory evoked potential (BAEP) (OR = 1.91, 95% CI = 1.02-3.50, P = 0.042) was independently associated with causative genetic variants in DD/ID children. Our findings enrich the variation spectrums of SNVs/Indels associated with DD/ID, highlight the value genetic testing for DD/ID children, stress the importance of BAEP screen in DD/ID children, and help to facilitate early diagnose, clinical management and reproductive decisions, improve therapeutic response to medical treatment.

Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient's cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E.

[Analysis of ADAR gene variants in a Chinese pedigree affected with Dyschromatosis symmetrica hereditaria in conjunct with developmental delay].

OBJECTIVE: To explore the clinical characteristics and genetic etiology for a Chinese pedigree affected with Dyschromatosis symmetrica hereditaria (DSH) in conjunct with developmental delay. METHODS: A child who had presented at the First Affiliated Hospital of Zhengzhou University on May 28 2021 for abnormal skin pigmentation of the extremities and growth retardation for over 2 years was selected as the study subject. Clinical data of the child and his pedigree (11 individuals from three generations) was collected. The child was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing. RESULTS: The child, a two-year-and-seven-month-old male, had hyper- and hypopigmentation on his hands, feet and face, in addition with delayed development. All members of his pedigree had typical presentation of DSH. A heterozygous c.2657G>A variant was found in exon 8 of the ADAR gene in the child, his mother, and elder sister. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PM1+PM2_Supporting+PP1+PP3). CONCLUSION: The c.2657G>A variant of the ADAR gene probably underlay the DSH in this pedigree.

TRAPPC11-CDG muscular dystrophy: Review of 54 cases including a novel patient.

The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD). We reviewed the phenotype of all reported individuals with TRAPPC11-opathies, including an additional Mexican patient with novel compound heterozygous missense variants in TRAPPC11 (c.751 T > C and c.1058C > G), restricted to the Latino population. In these 54 patients muscular dystrophy signs are common (early onset muscle weakness, increased serum creatine kinase levels, and dystrophic changes in muscle biopsy). They present two main phenotypes, one with a slowly progressive LGMD with or without GDD/ID (n = 12), and another with systemic involvement characterized by short stature, GDD/ID, microcephaly, hypotonia, poor speech, seizures, cerebral atrophy, cerebellar abnormalities, movement disorder, scoliosis, liver disease, and cataracts (n = 42). In 6 of them CMD was identified. Obstructive hydrocephaly, retrocerebellar cyst, and talipes equinovarus found in the individual reported here has not been described in TRAPPC11 deficiency. As in previous patients, membrane trafficking assays in our patient showed defective abnormal endoplasmic reticulum-Golgi transport as well as decreased expression of LAMP2, and ICAM-1 glycoproteins. This supports previous statements that TRAPPC11-opathies are in fact a congenital disorder of glycosylation (CDG) with muscular dystrophy.

Deciphering congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD) associated with constitutional CDK13 pathogenic variants - case report and literature review.

There are 21 human cyclin-dependent kinases which are involved in regulation of the cell cycle, transcription, RNA splicing, apoptosis and neurogenesis. Five of them: CDK4, CDK5, CDK6, CDK10 and CDK13 are associated with human phenotypes. To date, only 62 patients have been presented with mutated CDK13 gene. Those patients had developmental delay, dysmorphic facial features, feeding difficulties, different structural heart and brain defects. 36 of them had missense mutation affecting the protein kinase domain of CDK13. Our patient is the first person reported so far with a frameshift mutation which introduce premature stop codon in the first exon of the CDK13 gene. She has symptoms characteristic for congenital heart defects, facial dysmorphism and intellectual developmental disorder (CHDFIDD).

De novo variants in FRYL are associated with developmental delay, intellectual disability, and dysmorphic features.

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is expressed in multiple tissues, including the central nervous system where it is present in neurons but not in glia. Homozygous fry LoF mutation is lethal at various developmental stages, and loss of fry in mutant clones causes defects in wings and compound eyes. We next modeled four out of the five missense variants found in affected individuals using fry knockin alleles. One variant behaves as a severe LoF variant, whereas two others behave as partial LoF variants. One variant does not cause any observable defect in flies, and the corresponding human variant is not confirmed to be de novo, suggesting that this is a variant of uncertain significance. In summary, our findings support that fry is required for proper development in flies and that the LoF variants in FRYL cause a dominant disorder with developmental and neurological symptoms due to haploinsufficiency.

[Analysis of a child featuring global developmental delay and autism due to variant of TBR1 gene and a literature review].

OBJECTIVE: To explore the clinical characteristics and genetic basis for a child with global developmental delay and autism. METHODS: A child who had presented at West China Second University Hospital of Sichuan University on April 13, 2021 was selected as the study subject. Clinical manifestations, laboratory examination and result of genetic testing were analyzed. RESULTS: The main symptoms of the child had included cognitive, language and motor delay, autism and epilepsy. Electroencephalogram revealed multiple focal discharges in both waking and sleeping stages, with the remarkable one seen at the sleeping stage. Cranial MRI showed pachygyria and local cortical thickening, Whole exome sequencing (WES) revealed that the child has harbored a heterozygous c.1589_1595dup (p.Gly533Leufs*143) frameshifting variant in the TBR1 gene (OMIM 604616). Based on the guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PS2+PVS1_Supporting+PM2_Supporting). After treated with levetiracetam and rehabilitation training, the child did not have seizure in the past 5 months, and his motor development has also significantly improved. CONCLUSION: The c.1589_1595dup variant of the TBR1 gene probably underlay the disease in this patient.

Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features.

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.

Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.

General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.

Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly.

Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay. Additional symptoms include coordination or gait abnormalities, microcephaly, nonspecific brain malformations, hypotonia and seizures. Four individuals carry missense variants (three of them detected de novo) and three individuals carry null variants (two of them maternally inherited). Molecular modeling of the heterozygous missense variants suggests that the majority of them affect the globular structure of DOCK4. In vitro functional expression studies in transfected Neuro-2A cells showed that all missense variants impaired neurite outgrowth. Furthermore, Dock4 knockout Neuro-2A cells also exhibited defects in promoting neurite outgrowth. Our results, including clinical, molecular and functional data, suggest that loss-of-function variants in DOCK4 probable cause a variable spectrum of a novel neurodevelopmental disorder with microcephaly.

Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism.

OBJECTIVE: To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry. METHODS: We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein. RESULTS: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif. SIGNIFICANCE: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.

Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan-Herndon-Dudley Syndrome.

BACKGROUND: Deficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan-Herndon-Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X-linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease. CASES: Patient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs. CONCLUSIONS: We aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype-genotype correlations for this rare condition.

The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.

ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism.

ASXL3-related disorder, sometimes referred to as Bainbridge-Ropers syndrome, was first identified as a distinct neurodevelopmental disorder by Bainbridge et al. in 2013. Since then, there have been a number of case series and single case reports published worldwide. A comprehensive review of the literature was carried out. Abstracts were screened, relevant literature was analysed, and descriptions of common phenotypic features were quantified. ASXL3 variants were collated and categorised. Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%). The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene. Several gaps in our knowledge of this disorder were identified, namely, underlying pathophysiology and disease mechanism, disease contribution of missense variants, relevance of variant location, prevalence and penetrance data. Clinical information is currently limited by patient numbers and lack of longitudinal data, which this review aims to address.

Novel phenotype associated with homozygous likely pathogenic variant in the POP1 gene.

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1-related disorders.

Expanding the phenotype of PPP1R21-related neurodevelopmental disorder.

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of individuals with available brain imaging include delays in myelination, wavy outline of the bodies of the lateral ventricles, and slight prominence of the bodies of the lateral ventricles. PPP1R21-related neurodevelopmental disorder is associated with a consistent phenotype and should be considered in highly consanguineous individuals presenting with developmental delay/intellectual disability along with coarse facial features.

Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review.

CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.