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Background: Houge type of X-linked syndromic mental retardation (MRXSHG) is a type of X-linked condition which is mainly manifested as delayed development, mental retardation, epilepsy that begins at an early age, and delayed language acquisition. MRXSHG is a serious disorder with CNKSR2 variant and at least 34 variants have been identified in MRXSHG patients. However, the genotype-phenotype correlation and variants characteristics of CNKSR2 need further investigation and improvement., Methods: Two Chinese MRXSHG families were recruited, and their genetic causes were investigated using whole-exome sequencing (WES), Sanger sequencing, and bioinformatics analysis. To verify the impact of these variants, we used real-time PCR and minigenes consisting of exon 14, intron 14, and exon 15 from both the wild-type and the c.1658-3_1676del DNA sequences., Results: In this study, we reported two Chinese boys with MRXSHG and described some rare MRXSHG phenotypes, such as delayed bone age, slightly widened right fissure, and an underdeveloped right temporal lobe, characterized by reduced growth and volume compared to typical development. Two novel variants in CNKSR2 (c.1658-3_1676del and c.1102G > T, p.Gly368*) were identified in these cases. Minigenes results revealed that variant c.1658-3_1676del produced an aberrant spliceosome assembly., Conclusions: We identified two novel CNKSR2 variants in MRXSHG families, expanding the variant spectrum of CNKSR2, enriching MRXSHG-related phenotypes, and contributing to genetic counseling for MRXSHG patients., Competing Interests: Declarations. Ethics approval and consent to participate: This research was approved by the Review Board of Xiangya Hospital of Central South University (202103427) and conformed to the guidelines laid down in the Declaration of Helsinki. All parents and patients provided informed consent for the collection of biological samples. Written consent was waived. Consent for publication: Written informed consents were obtained from the family members, and they consented to participation in this study and to information publication. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

To explore the genetic cause of a four-generation severe intellectual disability in a Chinese family using nanopore sequencing and to provide genetic counseling and reproductive guidance for family members. Multiple genetic analyses of the proband and family members were performed, including chromosome karyotype analysis, whole exome sequencing, nanopore sequencing, PCR amplification, and Sanger sequencing. The results of G-binding karyotyping, CGG repeats for FMR1, GGC repeats for NOTCH2NCL, and trio-whole-exome sequencing were negative for the proband and his parents. Nanopore sequencing showed that the proband carried 12q24.33 microduplication (3.26 Mb) and 22q13.33 microdeletion (1.5 Mb). According to the guidelines of the American Society for Medical Genetics and Genomics (ACMG), the 22q13.33 microdeletion was classified as pathogenic, whereas the 12q24.33 microduplication was classified as a variant of uncertain significance (VUS). The precise karyotype and location of chromosomal breakpoints in the patient and family members were determined through PCR. According to the results of Sanger sequencing, a cryptic balanced translocation was detected in the proband's father. Additionally, informative SNPs were identified near the breakpoints for preimplantation genetic testing for structure rearrangement (PGT-SR) treatment by nanopore sequencing. We identified a cryptic unbalanced translocation in a large Chinese family with Phelan-McDermid syndrome (22q13.33 deletion syndrome) by nanopore sequencing. Nanopore sequencing can be a powerful tool for the genetic diagnosis of unexplained intellectual disability and the detection of precise breakpoints of chromosomal rearrangement in PGT-SR treatment., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics statement: The study related to human participants was reviewed and approved by the reproductive medicine ethics committee of Jiangxi maternal and child health hospital. All patients participated in this study were signed written informed consent. The research has been performed in accordance with the Helsinki Declaration., (© 2025. The Author(s).)

Objective: To explore the clinical phenotype and genetic characteristics of two siblings with intellectual disability., Methods: Clinical data and peripheral blood samples were collected from the proband, his younger sister and parents whom had presented at Wenzhou Central Hospital in February 2024. Low-coverage massively parallel copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the family. Candidate variants were verified by Sanger sequencing. Prenatal diagnosis was performed on a fetus upon the couple's subsequent pregnancy. The study was approved by the Medical Ethics Committee of Wenzhou Central Hospital (Ethic No. L2024-07-001)., Results: The proband was a 12-year-old boy who had presented with mental retardation and language delay. His 10-year-old sister also manifested delayed mental and motor development. Whole exome sequencing revealed that the proband and his sister had respectively harbored a novel heterozygous c.3549_3550del (p.Glu1183Aspfs*29) variant of the TRIP12 gene and a novel heterozygous c.99del (p.Ser34Alafs*38) variant of the GRIN2B gene. Sanger sequencing confirmed that both variants had a de novo origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PS2_Supporting+PM2_Supporting). Neither variant was found to be carried by the fetus upon prenatal diagnosis., Conclusion: Above variants probably underlay the mental disorders in the two siblings, and the concurrent occurrence of two novel pathogenic variants in a family has been extremely rare.

LINS1 is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in LINS1 gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (LINS1: c.274C > T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype-phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the LINS1 gene. In conclusions, our findings suggest the high clinical variations in the LINS1 variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China., (© 2024 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

F-box protein 11 (FBXO11) is a member of F-Box protein family, which has recently been proved to be associated with intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA, OMIM: 618089). In this study, 12 intellectual disability individuals from 5 Chinese ID families were collected, and whole exome sequencing (WES), sanger sequencing, and RNA sequencing (RNA-seq) were conducted. Almost all the affected individuals presented with mild to severe intellectual disability (12/12), global developmental delay (10/12), speech and language development delay (8/12) associated with a range of alternate features including increased body weight (7/12), short stature (6/12), seizures (3/12), reduced visual acuity (4/12), hypotonia (1/12), and auditory hallucinations and hallucinations (1/12). Distinguishingly, malformation was not observed in all the affected individuals. WES analysis showed 5 novel FBXO11 variants, which include an inframe deletion variant, a missense variant, two frameshift variants, and a partial deletion of FBXO11 (exon 22-23). RNA-seq indicated that exon 22-23 deletion of FBXO11 results in a new mRNA structure. Conservation and protein structure prediction demonstrated deleterious effect of these variants. The DEGs analysis revealed 148 differentially expressed genes shared among 6 affected individuals, which were mainly associated with genes of muscle and immune system. Our research is the first report of FBXO11-associated IDDFBA in Chinese individuals, which expands the genetic and clinical spectrum of this newly identified NDD/ID syndrome., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF., Methods: This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF., Results: Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein., Conclusions: Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus., (© 2024. The Author(s).)

Coffin-Siris syndrome (CSS) is a rare autosomal dominant inheritance disorder characterized by distinctive facial features, hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, hypotonia, hirsutism/hypertrichosis, sparse scalp hair and varying kind of congenital anomalies. CSS can easily be misdiagnosed as other syndromes or disorders with a similar clinical picture because of their genetic and phenotypic heterogeneity. We describde the genotype-phenotype correlation of one patient from a healthy Chinese family with a novel genotype underlying CSS, who was first diagnosed in the ophthalmology department as early-onset high myopia (eoHM). Comprehensive ophthalmic tests as well as other systemic examinations were performed on participants to confirm the phenotype. The genotype was identified using whole exome sequencing, and further verified the results among other family members by Sanger sequencing. Real-time quantitative PCR (RT-qPCR) technology was used to detect the relative mRNA expression levels of candidate genes between proband and normal family members. The pathogenicity of the identified variant was determined by The American College of Medical Genetics and Genomics (ACMG) guidelines. STRING protein-protein interactions (PPIs) network analysis was used to detect the interaction of candidate gene-related proteins with high myopia gene-related proteins. The patient had excessive eoHM, cone-rod dystrophy, coarse face, excessive hair growth on the face, sparse scalp hair, developmental delay, intellectual disability, moderate hearing loss, dental hypoplasia, patent foramen ovale, chronic non-atrophic gastritis, bilateral renal cysts, cisterna magna, and emotional outbursts with aggression. The genetic assessment revealed that the patient carries a de novo heterozygous frameshift insertion variant in the ARID1B c.3981dup (p.Glu1328ArgfsTer5), which are strongly associated with the typical clinical features of CSS patients. The test results of RT-qPCR showed that mRNA expression of the ARID1B gene in the proband was approximately 30% lower than that of the normal control in the family, suggesting that the variant had an impact on the gene function at the level of mRNA expression. The variant was pathogenic as assessed by ACMG guidelines. Analysis of protein interactions in the STRING online database revealed that the ARID1A protein interacts with the high myopia gene-related proteins FGFR3, ASXL1, ERBB3, and SOX4, whereas the ARID1A protein antagonizes the ARID1B protein. Therefore, in this paper, we are the first to report a de novo heterozygous frameshift insertion variant in the ARID1B gene causing CSS with excessive eoHM. Our study extends the genotypic and phenotypic spectrums for ARID1B-CSS and supplies evidence of significant association of eoHM with variant in ARID1B gene. As CSS has high genetic and phenotypic heterogeneity, our findings highlight the importance of molecular genetic testing and an interdisciplinary clinical diagnostic workup to avoid misdiagnosis as some disorders with similar manifestations of CSS., (© 2024. The Author(s).)

Objective: To analyze the clinical features and genetic etiology of 17 Chinese pedigrees affected with X-linked intellectual disability (XLID)., Methods: Seventeen pedigrees affected with unexplained intellectual disability which had presented at Henan Provincial People's Hospital from May 2021 to May 2023 were selected as the study subjects. Clinical data of the probands and their pedigree members were collected. Trio-whole exome sequencing (Trio-WES), Sanger sequencing and X chromosome inactivation (XCI) analysis were carried out. Pathogenicity of candidate variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics and co-segregation analysis., Results: The 17 probands, including 9 males and 8 females with an age ranging from 0.6 to 8 years old, had all shown mental retardation and developmental delay. Fourteen variants were detected by genetic testing, which included 4 pathogenic variants (MECP2: c.502C>T, MECP2: c.916C>T/c.806delG, IQSEC2: c.1417G>T), 4 likely pathogenic variants (MECP2: c.1157_1197del/c.925C>T, KDM5C: c.2128A>T, SLC6A8: c.1631C>T) and 6 variants of uncertain significance (KLHL15: c.26G>C, PAK3: c.970A>G/c.1520G>A, GRIA3: c.2153C>G, TAF1: c.2233T>G, HUWE1: c.10301T>A). The PAK3: c.970A>G, GRIA3: c.2153C>G and TAF1: c.2233T>G variants were considered as the genetic etiology for pedigrees 12, 14 and 15 by co-segregation analysis, respectively. The proband of pedigree 13 was found to have non-random XCI (81:19). Therefore, the PAK3: c.1520G>A variant may underlie its pathogenesis., Conclusion: Trio-WES has attained genetic diagnosis for the 17 XLID pedigrees. Sanger sequencing and XCI assay can provide auxiliary tests for the diagnosis of XLID.

NSUN2-intellectual disability syndrome, also known as intellectual disability type 5 (MRT5), is an autosomal recessive disorder that is characterized by intellectual disability (ID), postnatal growth retardation, dysmorphic facies, microcephaly, short stature, developmental delay, language impairment and other congenital abnormalities. The disease is caused by mutations in the NSUN2 gene, which encodes a tRNA cytosine methyltransferase that has an important role in spindle assembly during mitosis and chromosome segregation. In this study, we recruited a family that had two individuals with ID. Whole exome sequencing was performed to identify a homozygous frameshift variant (c.1171_1175delACCAT(p.Thr391fs*18*)) in NSUN2 (NM_017755.5) in the proband. The varint was confirmed as segregating in his affected brother and his parents by Sanger sequencing. The individuals that we described showed a similar dysmorphology profile to that associated with MRT5. To analyze the correlations between genotypes of NSUN2 and phenotypes of individuals with ID, we examined 17 variants and the associated phenotypes from 32 ID individuals in current and previous studies. We concluded that mutations in NSUN2 cause a wide range of phenotypic defects. Although some clinical manifestations were highly variable, the core phenotypes associated with NSUN2 mutations were dysmorphic facies, microcephaly, short stature, ID, growth restriction, language impairment, hypotonia and delayed puberty. Our study expands the genetic spectrum of NSUN2 mutations and helps to further define the genotype-phenotype correlations in MRT5., (© 2024. The Author(s).)

Background: Kabuki syndrome (KS) is a monogenic disorder leading to special facial features, mental retardation, and multiple system malformations. Lysine demethylase 6A, (KDM6A, MIM*300128) is the pathogenic gene of Kabuki syndrome type 2 (KS2, MIM#300867), which accounts for only 5%-8% of KS. Previous studies suggested that female patients with KS2 may have a milder phenotype., Method: We summarized the phenotype and genotype of KS2 patients who were diagnosed in Shanghai Children's Medical Center since July 2017 and conducted a 1:3 matched case-control study according to age and sex to investigate sex-specific differences between patients with and without KS2., Results: There were 12 KS2 cases in this study, and 8 of them matched with 24 controls. The intelligence quotient (IQ) score of the case group was significantly lower than that of the control group (P < 0.001). In addition, both the incidence of intellectual disability (ID) (IQ < 70) and moderate-to-severe ID (IQ < 55) were significantly higher in the case group than those in the control group. No sex-specific difference was found in the incidence of ID or moderate-to-severe ID between the female cases and female controls, whereas there was a significant difference between male cases and male controls. Furthermore, the rate of moderate-to-severe ID and congenital heart disease (CHD) was significantly higher in the male group than that in the female group., Conclusions: Our results showed that a sex-specific difference was exhibited in the clinical phenotypes of KS2 patients. The incidence of CHD was higher in male patients, and mental retardation was significantly impaired. However, the female patients' phenotype was mild., (© 2024. The Author(s).)

Objective: To analyze the clinical and genetic characteristics of ten Chinese pedigrees affected with 7q11.23 duplication syndrome., Methods: From December 2017 to January 2022, ten pedigrees diagnosed with 7q11.23 duplication syndrome at the First Affiliated Hospital of Zhengzhou University were enrolled as the study subjects. Clinical data of all subjects were collected, and some had subjected to copy number variation sequencing or single nucleotide polymorphism array to analyze the pattern of inheritance., Results: The probands had included six fetuses and four adolescents. Four of the six prenatal cases showed abnormal ultrasound indicators, including three with soft indicators and one with abnormal fetal structural development. The clinical phenotype of the four adolescent cases had included mental retardation, delayed language development, and attention deficit hyperactivity disorder. The size of the copy number variations had ranged from 1.31 to 1.42 Mb, involving the classic region of 7q11.23 duplication syndrome. Of these, five cases had undergone parental origin testing, three cases were de novo, and two were hereditary., Conclusion: Individuals with 7q11.23 duplication syndrome may show substantial clinical phenotypic heterogeneity, hence the affected families should be provided with pre-pregnancy consultation and reproductive guidance.

Background: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS., Methods: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed., Results: The Chinese PTHS patients presented with specific facial features and exhibited global developmental delay of wide severity range. The locus heterogeneity of the TCF4 gene in the patients was highlighted, emphasizing the significance of genetic studies for accurate diagnosis, albeit no significant correlations between genotype and phenotype were observed in this cohort. The study also reports the outcomes of patients who underwent therapeutic interventions, such as ketogenic diets and biomedical interventions., Conclusions: The findings of this retrospective analysis expand the phenotypic and molecular spectra of PTHS patients. The study underscores the need for a long-term prospective follow-up study to assess potential therapeutic interventions., (© 2024. The Author(s).)

Background: Intellectual disability (ID) is a con neurodevelopmental disorder in children. The genetic etiology of ID is complex, but more subtypes are defined due to the broad application of next-generation sequencing., Methods: Whole-exome sequencing (WES) and Sanger sequencing was applied in a family with ID., Results: We report a Chinese 7.5-year-old boy, born to non-consanguineous parents. He showed severe intellectual disability, seizures and autistic features. Two previously unreported variants in MBOAT7, c.669C>G (p.(Tyr223*)) and c.1095C>G (p.(Ser365Arg)) were identified by trio-WES. His mother is a heterozygous carrier of the c.1095C>G variant. The c.669C>G variant is a de novo variant which was undetected in his parents. By construction of the full-length cDNA of the patient's MBOAT7, we verified that these two variants were trans-compound heterozygous variants, which support the genetic etiology of this patient., Conclusion: This patient is the first Chinese case of intellectual developmental disorder (IDD), autosomal recessive 57 (OMIM:617188) with two unreported MBOAT7 variants., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Intellectual disability is a prevalent neurodevelopmental disorder, with the majority of affected children exhibiting global developmental delay before the age of 5 years. In recent years, certain children have been found to carry homozygous variations of the EEF1D gene, leading to autosomal recessive intellectual disability. However, the pathogenicity of compound heterozygous variations in this gene remains largely unknown., Methods: Trio whole-exome sequencing and copy number variation sequencing were done for the genetic etiological diagnosis of a 3-year and 11-month-old Chinese boy who presented with brachycephaly, severe to profound global developmental delay, and hypotonia in the lower limbs., Results: In this case, compound heterozygous variants of the EEF1D gene were found in the child through trio whole-exome sequencing; one was a splice variant (NM&#95;032378.6:c.1905+1G>A) inherited from his father, and the other was a nonsense variant (NM&#95;032378.6:c.676C>T) inherited from his mother. The nonsense variant leads to the production of a premature termination (p.Gln226*). These variations have the ability to explain the clinical phenotypes of the child., Conclusions: Our study expands the variation spectrum and provides compelling evidence for EEF1D as a candidate gene for autosomal recessive intellectual disability. However, due to the deficient number of reported cases, researchers need to further study EEF1D and supplement the clinical phenotypes and treatment measures., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

We report compound heterozygous variants in TOE1 in siblings of Chinese origin who presented with dyskinesia and intellectual disabilities. Our report provides further information regarding the etiology and pathogenesis of pontocerebellar hypoplasia type 7 syndrome (PCH7). Clinical manifestations were obtained, and genomic DNA was collected from family members. Whole-exome and Sanger sequencing were performed to identify associated genetic variants. Bioinformatics analysis was conducted to identify and characterize the pathogenicity of the heterozygous variants. Following long-term rehabilitation, both siblings showed minimal improvement, and their condition tended to progress. Whole-exome sequencing revealed two unreported heterozygous variants, NM&#95;025077: c.C553T (p.R185W) and NM&#95;025077: c.G562T (p.V188L), in the TOE1 gene mapped to 1p34.1. Sanger sequencing confirmed that the two variants in the proband and her brother were inherited from their parents. The NM&#95;025077: c.C553T (p.R185W) variant was inherited from the father, and the NM&#95;025077: c.G562T (p.V188L) variant was inherited from the mother. Although the two variants in the TOE1 gene have not been reported previously, they were associated with PCH7 based on integrated analysis. Thus, our report contributes to our knowledge regarding the etiology and phenotype of PCH 7., (© 2023 Wiley Periodicals LLC.)

Background: Pathogenic PAK1 variants were described to be causative of neurodevelopmental disorder with macrocephaly, seizures, and speech delay. Herein, we present a de novo PAK1 variant combine with a de novo terminal 1q microdeletion in a Chinese pediatric patient, aiming to provide more insights into the underlying genotype-phenotype relationship., Methods: Enrolled in this study was a 6-year-old girl with clinical features of global developmental delay, severe intellectual disability, speech delay, and seizures from Quanzhou region of China. Karyotype and chromosomal microarray analysis (CMA) were performed to detect chromosome abnormalities in this family. Whole exome sequencing (WES) was performed to investigate additional genetic variants in this family., Results: No chromosomal abnormalities were elicited from the entire family by karyotype analysis. Further familial CMA results revealed that the patient had a de novo 2.7-Mb microdeletion (arr[GRCh37] 1q44(246,454,321&#95;249,224,684) × 1]) in 1q44 region, which contains 14 OMIM genes, but did not overlap the reported smallest region of overlap (SRO) responsible for the clinical features in 1q43q44 deletion syndrome. In addition, WES result demonstrated a de novo NM&#95;002576: c.251C > G (p.T84R) variant in PAK1 gene in the patient, which was interpreted as a likely pathogenic variant., Conclusion: In this study, we identify a novel PAK1 variant associated with a terminal 1q microdeletion in a patient with neurodevelopmental disorder. In addition, we believe that the main clinical features may ascribe to the pathogenic variant in PAK1 gene in the patient., (© 2023. The Author(s).)

Background: Cohen syndrome (CS; OMIM 216550) is a rare syndrome with evident clinical heterogeneity. The diverse phenotype comprises early-onset hypotonia and developmental delays, intellectual disabilities, microcephaly, hypermobile joints, neutropenia, myopia, and characteristic facial features. The disease is rarely reported. Vacuolar Protein Sorting 13 Homolog B (VPS13B; OMIM 607817) is the only causative gene of CS., Methods: Blood samples sourced from both siblings and parents were sent to identify mutations by trio-WES, and changes in the patient's condition were understood through consultation data and follow-up., Results: We reported two siblings affected by developmental delay, microcephaly, intellectual disability, and facial features. The siblings' WES detected compound heterozygous variants in the exon region of VPS13B (NM&#95;017890): c.9337A>T and c.8551A>C., Conclusion: Two individuals were diagnosed with CS by genetic testing and clinical features. In addition, we conduct a brief review of the reports on the Chinese population with CS and reinforce the understanding of the correlation between genotype-phenotype., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: To explore the clinical features and genetic basis for a child with Bainbridge-Ropers syndrome (BRPS)., Methods: Clinical data of the child were retrospectively analyzed. Copy number variation sequencing (CNV-seq) and trio based whole exome sequencing (trio-WES) were carried out. Prenatal diagnosis was provided for a at risk fetus from the pedigree, and genotype phenotype correlation was summarized through a literature review., Results: The proband, a 6-year-old boy, has presented with feeding difficulties, specific craniofacial features, global developmental delay and intellectual disability, which has not improved after rehabilitation treatment. CNV-seq analysis of the patient showed no obvious abnormalities. A de novo heterozygous truncating variation, c.1448dupT (p.T484Nfs*5), was identified in the ASXL3 gene by trio-WES, which was a previously reported pathogenic variant. So far 14 Chinese patients with BRPS and ASXL3 variants have been reported. All patients have shown specific craniofacial features and delayed motor and speech development, and harbored 12 loss of function ASXL3 variants, which were de novo in origin and have clustered in exons 11 and 12 of the ASXL3 gene., Conclusion: The heterozygous frameshift c.1448dupT (p.T484Nfs*5) variant of the ASXL3 gene probably underlay the disorder in this patient. BRPS should be considered in infants with feeding difficulties, special craniofacial features, global developmental delay and hand anomalies, and WES can help to delineate the pathogenesis and establish the definite diagnosis.

Background: Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV) is a rare autosomal dominant syndrome, which is caused by the heterozygous germline loss-of-function variants in CTNNB1., Methods: We evaluated the clinical and genetic findings of 24 previously undescribed Chinese patients affected by CTNNB1-related disorders and explored the possible ethnicity-related phenotypic variations., Results: Twenty-one loss-of-function variants were identified within these 24 NEDSDV patients, including 14 novel CTNNB1 variants and 7 recurrent ones. The prominent clinical manifestations in our cohort are developmental delay/intellectual disability (100%), motor delay (100%), speech impairment (100%), dystonia (87.5%) and microcephaly (69.6%). The common facial dysmorphisms were consistent with previous reports, including wide nasal bridge (58.3%), bulbous nose (45.8%), long philtrum (45.8%) and thin upper lip (45.8%). In addition, 19 patients (79.2%) in our cohort had mild visual defects, while one affected individual (4.2%) had familial exudative vitreoretinopathy. Notably, we discovered that 20 patients (83.3%) exhibited various behavioral abnormalities, which is described in Chinese patients for the first time., Conclusion: We provided the largest known Chinese cohort with pathogenic CTNNB1 variants, which not only helps to expand the variant spectrum of CTNNB1 gene, but further delineates the typical phenotype of this disorder in Chinese population., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Autism spectrum disorder (ASD) is often accompanied by intellectual disability (ID). Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we tried to develop an analyzing pipeline for de novo mutations and possible pathways related to ID phenotype in ASD. Whole-exome sequencing (WES) was performed to screen de novo mutations and candidate genes in 79 ASD children together with their parents (trios). The de novo altering genes and relative pathways which were associated with ID phenotype were analyzed. The connection nodes (genes) of above pathways were selected, and the diagnostic value of these selected genes for ID phenotype in the study population was also evaluated., Results: We identified 89 de novo mutant genes, of which 34 genes were previously reported to be associated with ASD, including double hits in the EGF repeats of NOTCH1 gene (p.V999M and p.S1027L). Interestingly, of these 34 genes, 22 may directly affect intelligence quotient (IQ). Further analyses revealed that these IQ-related genes were enriched in protein synthesis, energy metabolism, and amino acid metabolism, and at least 9 genes (CACNA1A, ALG9, PALM2, MGAT4A, PCK2, PLEKHA1, PSME3, ADI1, and TLE3) were involved in all these three pathways. Seven patients who harbored these gene mutations showed a high prevalence of a low IQ score (&lt; 70), a non-verbal language, and an early diagnostic age (&lt; 4 years). Furthermore, our panel of these 9 genes reached a 10.2% diagnostic rate (5/49) in early diagnostic patients with a low IQ score and also reached a 10% diagnostic yield in those with both a low IQ score and non-verbal language (4/40)., Conclusion: We found some new genetic disposition for ASD accompanied with intellectual disability in this study. Our results may be helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted., (© 2022. The Author(s).)

Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To explore the genetic etiology for a Chinese pedigree affected with Alazami syndrome., Methods: Genomic DNA was extracted for 2 patients and 2 unaffected members from the pedigree. Whole exome sequencing was carried out to detect potential variant in the proband, and the result was verified by Sanger sequencing., Results: The proband and her sister were both found to harbor compound heterozygous variants of LARP7 gene, namely c.94A>T (p.Lys32*) and c.1141A>G (p.Lys381Glu), which were inherited from their father and mother, respectively. Both variants were predicted to be pathogenic based on bioinformatic analysis., Conclusion: The two variants of the LARP7 gene, both were unreported previously, probably underlay the Alazami syndrome in this pedigree. Above finding has expanded the mutational spectrum of the LARP7 gene.

Background: Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by developmental delay, intellectual disability, microcephaly, coarse face and hypoplastic nail of the fifth digits. Heterozygous variants of different BAF complex-related genes were reported to cause CSS, including ARID1A and SMARCA4. So far, no CSS patients with ARID1A and SMARCA4 variants have been reported in China., Objective: The aim of the current study was to identify the causes of two Chinese patients with congenital growth deficiency and intellectual disability., Methods: Genomic DNA was extracted from the peripheral venous blood of patients and their family members. Genetic analysis included whole-exome and Sanger sequencing. Pathogenicity assessments of variants were performed according to the guideline of the American College of Medical Genetics and Genomics. The phenotypic characteristics of all CSS subtypes were summarized through literature review., Results: We identified two Chinese CSS patients carrying novel variants of ARID1A and SMARCA4 respectively. The cases presented most core symptoms of CSS except for the digits involvement. Additionally, we performed a review of the phenotypic characteristics in CSS, highlighting phenotypic varieties and related potential causes., Conclusions: We reported the first Chinese CSS2 and CSS4 patients with novel variants of ARID1A and SMARCA4. Our study expanded the genetic and phenotypic spectrum of CSS, providing a comprehensive overview of genotype-phenotype correlations of CSS., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Objective: To explore the genetic basis for two unrelated patients with global developmental delay and coarse facial features., Methods: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing and Sanger sequencing were carried out to detect potential variants., Results: The two patients have presented with global developmental delay, coarse facies, muscular hypotonia, congenital heart disease, and pectus excavatum, and were found to harbor two de novo loss-of-function variants of the ARID1B gene, namely c.3586delC (p.Gln1196Serfs*15) and c.4954&#95;4957delACGT (p.Thr1652Glyfs*31). Both variants were unreported previously., Conclusion: The nonsense variants of the ARID1B gene probably underlay the etiology in these patients. Above finding has enriched the genotypic and phenotypic spectrum of the disease and provided a basis for prenatal diagnosis.

Background: Missense variants in MED12 are associated with MED12-related disorders. We aimed to clarify the molecular level changes and underlying pathogenic mechanism of a female patient in our study., Methods: We reported a Chinese girl with clinical characteristics similar to MED12-related disorders. Trio whole exome sequencing (WES) was performed to identify related pathogenic variant(s) and RNA sequencing (RNA-seq) was subsequently applied to evaluate the effect of identified variant(s) on mRNA splicing. Moreover, X-chromosome inactivation (XCI) assay based on AR and RP2 was performed to reveal the XCI pattern of the female patient., Results: The proband manifested mainly as mental retardation and language impairment. Trio WES revealed a novel heterozygous variant c.3354 + 5 G > A in intron 23 of MED12. RNA-seq identified two aberrant transcripts. XCI assay on AR revealed a homozygous result, while XCI based on RP2 showed random pattern in peripheral blood., Conclusion: In conclusion, we identified a novel variant c.3354 + 5 G > A by WES combined with RNA-seq, which extends the spectrum of MED12 variants and provide a basis for further genetic counseling. According to the result of two aberrant transcripts by RNA-seq, we speculate that our patient's milder clinical feature may be the consequence of multiple different transcripts., (Copyright © 2022. Published by Elsevier B.V.)

Coffin-Siris syndrome (CSS) is a neurodevelopmental disorder characterized by cognitive disability, coarse facial features, hypertrichosis, and somatic dysmorphic features. It is caused by mutations in the BAF-complex or SOX gene. Here, a Chinese woman presenting with neurodevelopmental delay, mild intellectual disability, speech delay, dysmorphic features, obesity, scoliosis, hypotonia, seizures, skin problems, hypokalemia, and endocrine dysfunction is described. Whole exome sequencing (WES) identified a heterozygous missense variant, c.2074G > C (p. Ala692Pro), in the SMARCC2 gene of the proband. Affecting chromatin structure, SMARCC2 plays an essential role in modulating cortical neurogenesis, and controlling cortical size and thickness. Moreover, it is associated with tumor suppression, and SMARCC2 mutations have been observed with high frequency in human cancers. While this is the second report of SMARCC2 mutations in patients with detailed phenotypes, this is the first describing the observation of electrolyte disturbances and endocrinopathy. These findings expanded the genetic and clinical spectrum of SMARCC2-related Coffin-Siris syndrome., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

KBG syndrome (OMIM #148050) is an autosomal dominant neurodevelopmental disorder characterized by the presence of macrodontia of the permanent central upper incisors, characteristic facial features, delay in development, intellectual disability, short stature, and various skeletal abnormalities. Over 200 affected individuals have been described worldwide, though underdiagnosis is suspected because the characteristic features are variably present and affected individuals can have a mild phenotype. This case series provides a summary of the clinical and molecular characteristics of 10 Chinese KBG syndrome patients recruited from a single center. To our knowledge, this is the first case series for Chinese KBG patients. This case series aimed at exploring potential ethnicity-related variability in KBG syndrome., (© 2022 Wiley Periodicals LLC.)

Skraban-Deardorff syndrome is a rare autosomal dominant genetic disease caused by variants in the WDR26 gene. Here, we report two Chinese patients diagnosed with Skraban-Deardorff syndrome caused by novel de novo, heterozygous pathogenic WDR26 variants c.977delA (p. 12 N326Ifs*2) and c.1020-2A>G (p. R340Sfs*29). Their clinical features were characterized by intellectual disability (ID), developmental delay, abnormal facial features and the absence of early-onset seizure, which expands the phenotype spectrum associated with Skraban-Deardorff syndrome. By comparing our cases with current reported cases of WDR26-related intellectual disability, we suggest that developmental delay, particularly in speech, and facial features including rounded palpebral fissures, depressed nasal root, full nasal tip and abnormal gums, represent the prominent clinical phenotypes for diagnosis of Skraban-Deardorff syndrome. Together, WDR26 variants and 1q41q42 deletions should feature prominently on the differential diagnosis of ID with distinctive facial features.

Background: With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism., Methods: The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation., Results: The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2 years and 6 months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334&#95;5335delAG (p. Arg1778Serfs*11) in the SON gene., Conclusion: Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome)., (© 2022 International Society for Developmental Neuroscience.)

Background: Bainbridge-Ropers syndrome (BRPS, OMIM #615485) was first identified in 2013 by Bainbridge et al. and is a neurodevelopment disorder characterized by failure to thrive, facial dysmorphism and severe developmental delay. BRPS is caused by heterozygous loss-of-function (LOF) variants in the additional sex combs-like 3 (ASXL3) gene. Due to the limited specific recognizable features and overlapping symptoms with Bohring-Opitz syndrome (BOS, OMIM #612990), clinical diagnosis of BRPS is challenging., Methods: In this study, a 2-year-8-month-old Chinese girl was referred for genetic evaluation of severe developmental delay. The reduced fetal movement was found during the antenatal period and bilateral varus deformity of feet was observed at birth. Whole-exome sequencing and Sanger sequencing were used to detect and confirm the variant., Results: A novel nonsense variant c.1063G>T (p.E355*) in the ASXL3 gene (NM&#95;030632.3) was identified in the proband and the clinical symptoms were compatible with BRPS. The parents were physical and genetic normal and prenatal diagnosis was requested for her pregnant mother with a negative Sanger sequencing result., Conclusion: The study revealed a de novo LOF variant in the ASXL3 gene and expanded the mutation spectrum for this clinical condition. By performing a literature review, we summarized genetic results and the clinical phenotypes of all BPRSs reported so far. More cases study may help to elucidate the function of the ASXL3 gene may be critical to understand the genetic aetiology of this syndrome and assist in accurate genetic counselling, informed decision making and prenatal diagnosis., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

SMG9-deficiency syndrome, also known as heart and brain malformation syndrome, is a very rare congenital genetic disorder mainly characterized by brain, heart, and growth and developmental abnormalities. This syndrome is an autosomal recessive disease resulting from mutations in the SMG9 gene, which encodes a critical component of nonsense-mediated mRNA decay. Thus far, only twelve SMG9 deficiency patients have been reported with five novel homozygous SMG9 mutations. The most frequent characteristic features of these patients are facial dysmorphism, severe global developmental delay, intellectual disability, congenital heart disease, growth restriction, microcephaly, and brain abnormalities. Herein, whole exome sequencing was performed to identify novel compound heterozygous SMG9 variants (NM&#95;019108.3: c.1318&#95;1319delAG (p.Ser440*) and c.947A>G (p.His316Arg)) in the proband, who exhibited syndromic intellectual disability. Mutations were confirmed as segregating in his affected sister and other unaffected family members by Sanger sequencing. The patients we describe here have a similar dysmorphology profile associated with SMG9-deficiency syndrome. Comparing the phenotype with that of patients in published reports, our patients can walk independently and their growth parameters are normal. In addition, short stature, failure to thrive, and microcephaly were not observed. Possible residual function of the H316R SMG9 variant could explain the milder phenotype observed in our patients. Our report is the first description of a non-consanguineous Chinese pedigree with novel compound heterozygous variants in the SMG9 gene. The molecular confirmation of the patient expands the genetic spectrum of SMG9-deficiency syndrome, and the manifestation of SMG9-deficiency syndrome in the patient provides additional clinical information regarding this syndrome., (© 2022. The Author(s).)

L1 syndrome, a complex X-linked neurological disorder, is caused by mutations in the L1 cell adhesion molecule (L1CAM) gene. L1CAM molecule is a member of immunoglobulin (Ig) superfamily of neural cell adhesion molecules (CAMs), which plays a pivotal role in the developing nervous system. In this study, a L1CAM gene exonic missense variant (c.1108G > A, p.G370R) was identified in two induced fetuses (abnormal fetuses), who presented corpus callosum agenesis accompanied with hydrocephalus. Clinical data, published literature, online database, and bioinformatic analysis suggest that the single-nucleotide variant of L1CAM gene is a likely pathogenic mutation. In vitro assays were performed to evaluate the effects of this variant. Based on NSC-34/COS-7 cells transfected with wild-type (L1-WT) and mutated (L1-G370R) plasmids, the L1CAM gene exonic missense variant (c.1108G > A, p.G370R) reduced cell surface expression, induced partial endoplasmic reticulum retention, affected posttranslational modification, and reduced protein's homophilic adhesive ability, but did not induce endoplasmic reticulum stress, which might probably associate with L1 syndrome. Finally, 35 isolated fetuses were screened for L1CAM gene variants by Sanger sequencing. These cases all prenatally suspected of corpus callosum agenesis accompanied with hydrocephalus, which may relate to L1 syndrome. Consequently, one L1CAM gene single missense variant (c.550C > T, p.R184W) was detected in one fetus. Our results provided evidence that the L1CAM gene missense variant (c.1108G > A, p.G370R) may relate to L1 syndrome. The findings of this study suggest a potential possibility of L1CAM gene screening for prenatal diagnoses for fetuses presented corpus callosum agenesis accompanied with hydrocephalus., (© 2021. The Author(s).)

Background: The study aimed to investigate the clinical and genetic features of Rahman syndrome caused by HIST1H1E gene mutations., Methods: We retrospectively analyzed the clinical information and genetic testing results of a Rahman syndrome family in an outpatient clinic in August 2020 and summarized the clinical characteristics of the HIST1H1E gene mutations in conjunction with peer-reviewed reports., Results: A 4-year-old boy was diagnosed with severe developmental delay and with specific features (large head, full cheeks, high hairline, low-set ear, sparse eyebrows, and short neck) similar to his mother (mild intellectual disability, high hairline, reduced hair, ptosis, sagging skin, and hyperkeratosis) and premature aging. Trio whole exome sequencing (WES) revealed a novel maternal c.368dup (p.G124Rfs*72) heterozygous mutation in the HIST1H1E gene. There have been only a few reported cases with mainly de novo mutations. Only six peer-reviewed articles in English and one in Chinese have been published regarding this syndrome. From 48 children with Rahman syndrome, 21 were males and 27 were females encompassing 25 mutations in the HIST1H1E gene. All mutations located in C-terminal tail were frameshift mutations leading to premature protein termination., Conclusion: Rahman syndrome, caused by the HIST1H1E gene mutation, is a rare autosomal dominant disorder in which the patient has an unusual facial appearance with high hairline and full cheeks, and clinical manifestations of mild to severe intellectual disability, motor delay and speech delay. Genetic testing may assist in the diagnosis of these patients. This diagnosis will permit early speech rehabilitation to improve their quality of life., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: To investigate the clinical characteristics and genetic basis for a child with Keppen-Lubinsky syndrome (KPLBS)., Methods: Trio-whole exome sequencing (Trio-WES) was carried out for the proband and her parents. Candidate variant was verified by Sanger sequencing and bioinformatic analysis., Results: The child has featured peculiar facies including large eyes, alar hypoplasia, microretrognathia, premature aging appearance in addition with growth delay and mental retardation. Trio-WES has identified that she has carried a de novo variant of the KCNJ6 gene, namely c.460G>C (p.Gly154Arg). The variant has not been recorded in the database. Prediction of protein structure indicated that the variant may affect the potassium ion selective filtration structure channel in the transmembrane region of KCNJ6 protein, which may result in up regulation of the function of the channel., Conclusion: The de novo c.460G>C (p.Gly154Arg) variant of the KCNJ6 gene probably underlay the KPLBS in this child. Above finding has enriched the genotypic and phenotype spectrum of this syndrome.

Background: Variants in the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na + ,K + )/H + exchanger 6 (NHE6) gene have been linked to epilepsy, speech loss, truncal ataxia, hyperkinesia, and postnatal microcephaly., Methods: In the present study, we evaluated genetic alterations in a 3-year-old Chinese boy displayed features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention loss, ataxia, and cerebellar atrophy and his healthy family using WES method. The identified variant was further confirmed by Sanger sequencing method. Finally, minigene assays were used to verify whether the novel SLC9A6 intronic variant influenced the normal splicing of mRNA., Results: We identified a novel hemizygous splicing variant [NM&#95;001042537.1: c.1463-1G>A] in SLC9A6 by trio-based exome sequencing. The minigene expression in vitro confirmed the splicing variant altered a consensus splice acceptor site of SLC9A6 intron 11, resulting in skipping over exon 12., Conclusions: Our finding extends the catalog of pathogenic intronic variants affecting SLC9A6 pre-mRNA splicing and provides a basis for the genetic diagnosis of CS., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Woodhouse-Sakati syndrome (WSS) (OMIM#241080) is a rare multi-system autosomal recessive disease with homozygous mutation of the DCAF17 gene. The main features of WSS include diabetes, hypogonadism, alopecia, deafness, intellectual disability and progressive extrapyramidal syndrome. We identified a WSS family with a novel DCAF17 gene mutation type in China. Two unconsanguineous siblings from the Chinese Han family exhibiting signs and symptoms of Woodhouse-Sakati syndrome were presented for evaluation. Whole-exome sequencing revealed a homozygous deletion NM&#95;025000.4:c.1488&#95;1489delAG in the DCAF17 gene, which resulted in a frameshift mutation that led to stop codon formation. We found that the two patients exhibited low insulin and C-peptide release after glucose stimulation by insulin and C-peptide release tests. These findings indicate that the DCAF17 gene mutation may cause pancreatic β cell functional impairment and contribute to the development of diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Shi, Zheng, Chen, Wang, Xiao, Cui, Qiu, Zhu and Li.)

Background: Neurodevelopmental disorder with absent language and variable seizures (NEDALVS, OMIM # 618707) is a newly described autosomal dominant condition caused by heterozygous de novo mutation in WASF1 gene. WASF1 is a key component of the WAVE regulatory complex (WRC) required for actin polymerization. So far, only 3 distinct truncating variants clustering at the WCA domain, 3 missense variants localized to the meander region and a copy number variant (CNV) of WASF1 have been identified among 11 NEDALVS cases previously reported., Case Report: We report a pediatric patient carrying novel de novo heterozygous missense variant (NM&#95;003931.2: c.481T > C, p.Trp161Arg) in WASF1 gene. During the first hospitalization at age of 5.5 months, the patient was initially diagnosed with infantile spasms, developmental delay (DD) and microcephaly due to nodding-like epileptic spasms in clusters and hypsarrhythmia on video-electroencephalography, lacking head control and body rollover, and abnormal head circumference 39 cm (<-2SD). The genetic diagnosis with a causal WASF1 variant detected by trio exome sequencing indicated the rare NEDALVS., Literature Review: All the reported NEDALVS cases published in the PubMed English literature were reviewed to summarize the genetic and phenotypic spectrum of this novel disorder., Conclusion: We describe the third patient with a recurrently mutated amino acid site at p.Trp161 in WASF1, currently the 12th patient with NEDALVS. This hotspot missense variant and the truncating variants in WASF1 lead to similar phenotypic patterns with core features of severe DD/ID, and seizures, hypotonia, and microcephaly frequently observed. Our finding expands the WASF1 mutation spectrum and confirms the de novo hotspot missense variant at p.Trp161, further supporting the association of the novel NEDALVS with WASF1 gene and the actin regulatory pathway., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To describe a family with intellectual developmental disorder with autism and speech delay (IDDAS) caused by a splice variant of TBR1 gene., Methods: A pregnant women with mental retardation, who also had a family history of mental retardation, was admitted to Prenatal Diagnosis Center of WanBei Coal and Electricity Group General Hospital Corporation in April 2019. Molecular genetic tests were performed on the pregnant women and ten other family members to analyze the pathogenic genotype. Functional assays of the pathogenic variant was carried out by minigene technology. With the determination of the genotype, prenatal diagnosis was carried out by amniotic fluid sampling., Results: Through whole exome sequencing, a novel splicing variant (c.1129-1G>C) was identified in the TBR1 gene of the proband, which has co-segregated with the disease phenotype in the family. The results of minigene assay showed abnormal splicing of exon 5. The variant was not detected in the fetal amniotic fluid. Fetal growth and development were normal one year after the birth., Conclusion: The c.1129-1G>C variant of the TBR1 probably underlay the disease in of the pedigree. Timely prenatal genetic diagnosis and consultation can help to stop the transmission of the pathogenic variant.

Background: The Raynaud-Claes type of X-linked syndromic mental retardation (MRXSRC) is a very rare condition, by intellectual disability ranged from borderline to profound, impaired language development, brain abnormalities, facial dysmorphisms and seizures. MRXSRC is caused by variants in CLCN4 which encodes the 2Cl - /H + exchanger ClC-4 prominently expressed in brain., Case Presentation: We present a 3-year-old Chinese girl with intellectual disability, dysmorphic features, brain abnormalities, significant language impairment and autistic features. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, a mega cisterna magna and ventriculomegaly. Whole exome sequencing (WES) was performed to detect the molecular basis of the disease. It was confirmed that this girl carried a novel heterozygous missense variant (c.1343C > T, p.Ala448Val) of CLCN4 gene, inherited from her mother. This variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools., Conclusion: Our investigation expands the phenotype spectrum for CLCN4 variants with syndromic X-linked intellectual disability, which help to improve the understanding of CLCN4-related intellectual disability and will help in genetic counselling for this family., (© 2021. The Author(s).)

Background: It has been reported that de novo heterozygous variants of DEAF1 can cause DEAF1-associated neurodevelopmental disorder. The purpose of this article is to explore the clinical and genetic characteristics of Chinese patients harboring de novo DEAF1 variants., Methods: We assembled a cohort of six unrelated patients with de novo variants in DEAF1. Clinical and genetic features of these patients were summarized., Results: Each child showed intellectual disability (ID)/ global developmental delay (GDD). Severe language impairment was prominent. Behavior problems, seizures, sleep disturbance, and a high pain threshold were common features. DEAF1-related seizures were reported to be difficult to treat or intractable. Seizures in our cohort were almost all treatable. Valproic acid was the most commonly used drug. Five heterozygous missense mutations of DEAF1 gene were identified, three of which (p.W234C, p.L203P, p.H275Q) were not published in literature before., Conclusion: Mutations of DEAF1 gene should be considered in ID/GDD patients with a nonspecific phenotype, comprising intellectual disability, prominent speech delay, abnormal behaviors, especially autism. In our study, DEAF1-related epilepsy is completely treatable in Eastern-Asian individuals when compared to patients in other regions, and valproic acid can be used as a first choice. The knowledge of DEAF1-related neurodevelopmental disorder and the de novo variant database of DEAF1 were expanded., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of chronic encephalopathies characterized by epilepsy with comorbid intellectual disability that are frequently associated with de novo nonsynonymous coding variants in ion channels, cell-surface receptors, and other neuronally expressed genes. Mutations in TRPM3 were identified as the cause of DEE. We report a novel patient with DEE carrying a de novo missense mutation in TRPM3, p.(S1202T); this missense mutation has never been reported., Case Presentation: A 7-year and 2-month-old Chinese patient who had recurrent polymorphic seizures was clinically diagnosed with DEE. A de novo missense mutation in TRPM3, which has not yet been reported, was identified in this case. The patient had a clinical phenotype consistent with previous reports., Conclusions: These findings could expand the spectrum of TRPM3 mutations and might also support that de novo substitutions of TRPM3 are a cause of DEE.

Purpose: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders., Methods: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations., Results: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts., Conclusion: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. Herein, we reported a 3-year-old girl evaluated for facial dysmorphism (long and connected eyebrows, big mouth, wide nasal bridge, high palatine arch, low set ears, and thin hair), growth retardation, intellectual disability, and language delay. Chromosomal microarray analysis revealed an 8.1-Mb deletion within 6q25.1-q25.3 ([hg19] chr6: 152,307,705-160,422,834) comprising 31 genes. Dysmorphic features, microcephaly, intellectual disability, language delay, growth retardation, and corpus callosum dysgenesis were commonly reported. Hence, 6q25 microdeletion is a rare condition. In patients with dysmorphic features, microcephaly, growth retardation, intellectual disability, language delay and corpus callosum dysgenesis, 6q25 microdeletion should be considered in the differential diagnosis and chromosomal microarray analysis should be performed to confirm the diagnosis.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes. The aim of this study was to describe the phenotypic-genetic spectrum of SYNE1-related ARCA1 patients in the Chinese population. We screened 158 unrelated patients with autosomal recessive or sporadic ataxia for variants in SYNE1 using next-generation sequencing. Pathogenicity assessment of SYNE1 variants was interpreted according to the American College of Medical Genetics standards and guidelines. We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families, including nine novel variants and one reported variant. Of the six index patients, two patients showed the classical pure cerebellar ataxia, while four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation. The variants associated with motor neuron or cognition involvement tend to be located in the C-terminal region of SYNE1 protein, compared with the variants related to pure cerebellar ataxia. Our data indicating SYNE1 mutation is one of the more common causes of recessive ataxia in the Chinese population. The use of next-generation sequencing has enabled the rapid analysis of recessive ataxia and further expanded our understanding of genotype-phenotype correlation.

Background: 22q11.2 variation is a significant genetic factor relating to development delay and/or intellectual disability. However, the prevalence, genetic characteristics and clinical phenotype in Chinese patients are unknown., Methods: In total 6034 patients with development delay and/or intellectual disability were screened by multiplex ligation-dependent probe amplification (MLPA) P245 and G-band karyotyping. The positive patients with 22q11.2 imbalance were confirmed by MLPA P250 assay., Results: 52 (0.86%) patients were found to carry different levels of 22q11.2 variations, in which 37 cases (71.2%) had heterozygous deletions, whereas 15 (28.8%) had heterogeneous duplications. 34 cases (65.4%) carried typical imbalance from low copy repeat (LCR) 22 A to D. The other cases had atypical variations, relating to LCR22 A-B, LCR22 C-D, LCR22 B-D, LCR22 D-E, LCR22 E-F and LCR22 B-F region. The phenotypes of these 52 patients were variable, including development delay, language delay, facial anomalies, heart defects, psychiatric/behavior problems, epilepsy, periventricular leukomalacia, hearing impairment, growth delay etc. CONCLUSION: These data revealed the prevalence and variability of 22q11.2 genomic imbalance in Chinese patients with development delay and/or intellectual disability. It suggested that genetic detection of 22q11.2 is necessary, especially for the patients with mental retardation and development disorders, which deserves the attention of all pediatricians in their daily work.

Rationale: Warburg Micro syndrome is a rare, autosomal recessive disorder characterized by multiple organ abnormalities involving the ocular, nervous, and genital systems. This case report describes a novel mutation in the RAB3GAP1 gene associated with Warburg Micro syndrome., Patient Concerns: A 6-month-old female infant with bilateral congenital cataracts and developmental delay was referred to our department for further assessment. She presented with facial dysmorphic features, including a prominent forehead, microphthalmia, wide nasal bridge, relatively narrow mouth, large anteverted ears, and micrognathia., Diagnoses: The patient was diagnosed with Warburg Micro syndrome based on clinical manifestations, as well as a novel homozygous mutation in RAB3GAP1: c.75-2A>C. Both parents were identified as heterozygotic carriers of this mutation., Interventions: Bilateral cataract extraction and anterior vitrectomy were performed at age 6 months, followed by physical rehabilitation. Convex lenses were used to protect the eyes postoperatively until intraocular lens implantation., Outcomes: Although the patient received physical rehabilitation, she suffered global developmental delay., Lessons: The c.75-2A>C mutation in RAB3GAP1 expands the spectrum of known mutations in this gene, and it may be associated with Warburg Micro syndrome. Genetic counselors may wish to take this finding into consideration, especially given the poor prognosis associated with the disease., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Copy number variants (CNVs) are responsible for many patients with short stature of unknown etiology. This study aims to analyze clinical phenotypes and identify pathogenic CNVs in a patient with short stature, intellectual disability, craniofacial deformities, and anal imperforation., Methods: G-banded karyotyping and chromosomal microarray analysis (CMA) was used on the patient to identify pathogenic causes. Fluorescence in situ hybridization (FISH) was applied to explore the abnormal genetic origin. Literatures were searched using identified CNVs as keywords in the PubMed database to perform genotype-phenotype analysis., Results: Cytogenetic analysis revealed a normal karyotype 46,XY. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3. FISH confirmed that the abnormal chromosomes were inherited from paternal balanced translocation. We compared phenotypes of our patient with 6 patients with 8q24.3 duplication and 7 cases with 21q22.3 deletion respectively., Conclusions: A novel 8q24.3 duplication and 21q22.3 deletion was identified in a Chinese patient. Genotype-phenotype analysis demonstrated that patients with 8q24.3 duplication and 21q22.3 deletion had specific facial features, intellectual disability, short stature, and multiple malformations., (© 2021 S. Karger AG, Basel.)

Purpose: To elucidate the genetic cause of intellectual deficiency and/or congenital malformations in two parental reciprocal translocation carriers and provide appropriate strategies of assisted reproductive therapy (ART)., Materials and Methods: Two similar couples having a child with global developmental delay/intellectual disability symptoms attended the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha, China) in 2017 and 2019, respectively, in order to determine the cause(s) of the conditions affecting their child and to seek ART to have a healthy baby. Both of the healthy couples were not of consanguineous marriage, denied exposure to toxicants, and had no adverse life history. This study was approved by the Institutional Ethics Committee of the Reproductive & Genetic Hospital of CITIC-Xiangya, and written informed consent was obtained from the parents. Genetic diagnoses were performed by karyotype analysis, breakpoint mapping analysis of chromosomal translocation(s), single-nucleotide polymorphism (SNP) microarray analysis, and whole-exome sequencing (WES) for the two children and different appropriate reproductive strategies were performed in the two families., Results: Karyotype analysis revealed that both patients carried parental reciprocal translocations [46,XY,t(7;16)(p13;q24)pat and 46,XY,t(13;17)(q12.3;p11.2)pat, respectively]. Follow-up breakpoint mapping analysis showed no interruption of associated genes, and SNP microarray analysis identified no significant copy number variations (CNVs) in the two patients. Moreover, WES results revealed that patients 1 and 2 harbored candidate compound heterozygous mutations of MCOLN1 [c.195G>C (p.K65N) and c.1061G>A (p.W354*)] and MCPH1 [c.877A>G (p.S293G) and c.1869&#95;1870delAT (p.C624*)], respectively, that were inherited from their parents and not previously reported. Furthermore, the parents of patient 1 obtained 10 embryos during ART cycle, and an embryo of normal karyotype and non-carrier of observed MCOLN1 mutations according to preimplantation genetic testing for structural rearrangement and monogenic defect was successfully transferred, resulting in the birth of a healthy boy. The parents of patient 2 chose to undergo ART with donor sperm to reduce the risk of recurrence., Conclusions: Systematic genetic diagnosis of two carriers of inherited chromosomal translocations accompanied by clinical phenotypes revealed their cause of disease, which was critical for genetic counseling and further ART for these families.

Objectives: Oliver-McFarlane syndrome (OMCS) is an autosomal recessive inherited disease resulting from PNPLA6 mutations that results in intellectual impairment and profound short stature. To obtain a better understanding of the genotype-phenotype correlations for PNPLA6-related disorders, we reported the 14th OMCS case and summarized all the reported cases of OMCS., Methods: We collected clinical biochemical and data and brain MRI data and used whole-exon gene detection and analysis tools to evaluate the pathogenicity of the variants, including PolyPhen-2 and Mutation Taster, and we also generated three-dimensional protein structures and visualized the effects of altered residues with I-TASSER and PyMOL Viewer software., Results: The patient presented with trichomegaly and multiple pituitary hormone deficiencies. Brain MRI showed small pituitary and bilateral paraventricular leukomalacia. Novel variants (c.1491G > T and c.3367G > A) in the PNPLA6 gene were detected in the proband and verified by direct sequencing. Amino acid residues of Gln497 and Gly1123 are predicted to be damaging and destroy the three-dimensional protein structures of the protein. In follow-up, this patient could neither walk nor hold his head erect and had not spoken one word at the age of one year and ten months. Moreover, there is no obvious hot spot mutation in any of the reported allelic variants. Interestingly, the majority of mutations are located in the phospholipid esterase domain, which is responsible for esterase activity., Conclusions: We identified two novel variants of the PNPLA6 gene in an OMCS patient, which will help to better understand the function of PNPLA6 and genotype-phenotype correlations for PNPLA6-related disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Agenesis of the corpus callosum (ACC) is a relatively common brain malformation in children with developmental disabilities, caused by mutations in many genes. These genetic causes are characterized by their extreme heterogeneity with more than 300 causative genes identified to date., Case Report: We describe two new cases from a three-generation family with ACC and a de novo mutation of the sonic hedgehog (SHH) gene. The affected family members had mild intellectual disability, broad forehead, and widely spaced eyes. A next-generation sequencing (NGS) approach revealed a stop-gain mutation (NM&#95;000193.2:c.1300&#95;1301insA p.Trp434Ter) of the SHH gene; it is the first family to report ACC associated with a single SHH gene mutation., Conclusion: ACC with mild intellectual disability and facial dysmorphism may be caused by a mutation in SHH, but further research investigating the genotype-phenotype correlation of SHH mutations is required., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)