An adolescent case of ASXL3-related disorder with delayed onset of feeding difficulty.

BACKGROUND: ASXL3-related disorder, first described in 2013, is a genetic disorder with an autosomal dominant inheritance that is caused by a heterozygous loss-of-function variant in ASXL3. The most characteristic feature is neurodevelopmental delay with consistently limited speech. Feeding difficulty is a main symptom observed in infancy. However, no adolescent case has been reported. CASE PRESENTATION: A 14-year-old girl with ASXL3-related syndrome was referred to our hospital with subacute onset of emotional lability. Limbic encephalitis was ruled out by examination; however, the patient gradually showed a lack of interest in eating, with decreased diet volume. Consequently, she experienced significant weight loss. She experienced no symptoms of bulimia, or food allergy; therefore, avoidant/restrictive food intake disorder (ARFID) was clinically suspected. CONCLUSIONS: We reported the first case of ASXL3-related disorder with adolescent onset of feeding difficulty. ARFID was considered a cause of the feeding difficulty.

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.

Examining the neurodevelopmental and motor phenotypes of Bohring-Opitz syndrome (ASXL1) and Bainbridge-Ropers syndrome (ASXL3).

Background: Chromatin Modifying Disorders (CMD) have emerged as one of the most rapidly expanding genetic disorders associated with autism spectrum disorders (ASD). Motor impairments are also prevalent in CMD and may play a role in the neurodevelopmental phenotype. Evidence indicates that neurodevelopmental outcomes in CMD may be treatable postnatally; thus deep phenotyping of these conditions can improve clinical screening while improving the development of treatment targets for pharmacology and for clinical trials. Here, we present developmental phenotyping data on individuals with Bohring-Optiz Syndrome (BOS - ASXL1) and Bainbridge-Ropers Syndrome (BRS - ASXL3) related disorders, two CMDs highly penetrant for motor and developmental delays. Objectives: To phenotype the motor and neurodevelopmental profile of individuals with ASXL1 and ASXL3 related disorders (BOS and BRS). To provide a preliminary report on the association of motor impairments and ASD. Methods: Neurodevelopmental and motor phenotyping was conducted on eight individuals with pathogenic ASXL1 variants and seven individuals with pathogenic ASXL3 variants, including medical and developmental background intake, movement and development questionnaires, neurological examination, and quantitative gait analysis. Results: Average age of first developmental concerns was 4 months for individuals with BOS and 9 months in BRS. 100% of individuals who underwent the development questionnaire met a diagnosis of developmental coordination disorder. 71% of children with BOS and 0% of children with BRS noted movement difficulty greatly affected classroom learning. Participants with BRS and presumed diagnoses of ASD were reported to have more severe motor impairments in recreational activities compared to those without ASD. This was not the case for the individuals with BOS. Conclusion: Motor impairments are prevalent and pervasive across the ASXL disorders with and without ASD, and these impairments negatively impact engagement in school-based activities. Unique neurodevelopmental and motor findings in our data include a mixed presentation of hypo and hypertonia in individuals with BOS across a lifespan. Individuals with BRS exhibited hypotonia and greater variability in motor skills. This deep phenotyping can aid in appropriate clinical diagnosis, referral to interventions, and serve as meaningful treatment targets in clinical trials.

ASXL3 gene mutations inhibit cell proliferation and promote cell apoptosis in mouse cardiomyocytes by upregulating lncRNA NONMMUT063967.2.

Congenital heart disease (CHD) is a serious condition with unknown etiology. In a recent study, a compound heterozygous mutation (c.3526C > T [p.Arg1176Trp] and c.4643A > G [p.Asp1548Gly]) in the ASXL3 gene was identified, which is associated with CHD. This mutation was overexpressed in HL-1 mouse cardiomyocyte cells, leading to increased cell apoptosis and decreased cell proliferation. However, whether this effect is mediated by long noncoding RNAs (lncRNAs) is yet to be determined. We identified the differences among lncRNA and mRNA profiles in mouse heart tissues using sequencing to explore this issue. We detected HL-1 cell proliferation and apoptosis through CCK8 and flow cytometry. Fgfr2, lncRNA, and Ras/ERK signaling pathway expressions were evaluated using quantitative real time polymerase chain reaction (qRT-PCR) and western blot (WB) assays. We also conducted functional investigations by silencing lncRNA NONMMUT063967.2. The sequencing revealed significant changes in lncRNA and mRNA profiles, with the expression of lncRNA NONMMUT063967.2 being significantly promoted in the ASXL3 gene mutations group (MT) while the expression of Fgfr2 being downregulated. The in vitro experiments showed that ASXL3 gene mutations inhibited the proliferation of cardiomyocytes and accelerated cell apoptosis by promoting the expression of lncRNAs (NONMMUT063967.2, NONMMUT063918.2, and NONMMUT063891.2), suppressing the formation of FGFR2 transcripts, and inhibiting the Ras/ERK signaling pathway. The decrease in FGFR2 had the same effect on the Ras/ERK signaling pathway, proliferation, and apoptosis in mouse cardiomyocytes as ASXL3 mutations. Further mechanistic studies revealed that suppression of lncRNA NONMMUT063967.2 and overexpression of FGFR2 reversed the effects of the ASXL3 mutations on the Ras/ERK signaling pathway, proliferation, and apoptosis in mouse cardiomyocytes. Therefore, ASXL3 mutation decreases FGFR2 expression by upregulating lncRNA NONMMUT063967.2, inhibiting cell proliferation and promoting cell apoptosis in mouse cardiomyocytes.

Targeted sequencing and clinical strategies in children with autism spectrum disorder: A cohort study.

Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with genetic and clinical heterogeneity. Owing to the advancement of sequencing technologies, an increasing number of ASD-related genes have been reported. We designed a targeted sequencing panel (TSP) for ASD based on next-generation sequencing (NGS) to provide clinical strategies for genetic testing of ASD and its subgroups. Methods: TSP comprised 568 ASD-related genes and analyzed both single nucleotide variations (SNVs) and copy number variations (CNVs). The Autism Diagnostic Observation Schedule (ADOS) and the Griffiths Mental Development Scales (GMDS) were performed with the consent of ASD parents. Additional medical information of the selected cases was recorded. Results: A total of 160 ASD children were enrolled in the cohort (male to female ratio 3.6:1). The total detection yield was 51.3% for TSP (82/160), among which SNVs and CNVs accounted for 45.6% (73/160) and 8.1% (13/160), respectively, with 4 children having both SNVs and CNV variants (2.5%). The detection rate of disease-associated variants in females (71.4%) was significantly higher than that in males (45.6%, p = 0.007). Pathogenic and likely pathogenic variants were detected in 16.9% (27/160) of the cases. SHANK3, KMT2A, and DLGAP2 were the most frequent variants among these patients. Eleven children had de novo SNVs, 2 of whom had de novo ASXL3 variants with mild global developmental delay (DD) and minor dysmorphic facial features besides autistic symptoms. Seventy-one children completed both ADOS and GMDS, of whom 51 had DD/intellectual disability (ID). In this subgroup of ASD children with DD/ID, we found that children with genetic abnormalities had lower language competence than those without positive genetic findings (p = 0.028). There was no correlation between the severity of ASD and positive genetic findings. Conclusion: Our study revealed the potential of TSP, with lower cost and more efficient genetic diagnosis. We recommended that ASD children with DD or ID, especially those with lower language competence, undergo genetic testing. More precise clinical phenotypes may help in the decision-making of patients with genetic testing.

Familial Bainbridge-Ropers syndrome: Report of familial ASXL3 inheritance and a milder phenotype.

De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder.

De novo nonsense variant in ASXL3 in a Chinese girl causing Bainbridge-Ropers syndrome: A case report and review of literature.

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_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.

A case of Bainbridge-Ropers syndrome with breath holding spells and intractable epilepsy: challenges in diagnosis and management.

BACKGROUND: Bainbridge-Ropers syndrome is caused by monoallelic ASXL3 variants on chromosome 18. Clinical features include dysmorphic facies, developmental delay, intellectual disability, autistic traits, hypotonia, failure to thrive, seizures and hyperventilation. Breath-holding spells with choreathetoid movements have been previously described. CASE PRESENTATION: We describe an 11-year old boy who has daily intractable seizures reported since birth, developmental delay, autistic features and feeding difficulties. He was eventually found to have de novo, heterozygous pathogenic variant (c.1612G > T, p.E538*) in the ASXL3 gene. He has frequent episodes of breath-holding accompanied by dystonic posturing with right leg extension and head turning without ictal EEG correlate. The breath-holding spells have been refractory to several medication trials including iron supplementation, acetazolamide, and desipramine. CONCLUSIONS: This case represents a more severe phenotype of Bainbridge-Ropers Syndrome than previously described with refractory breath-holding spells with dystonia, intractable epilepsy, and progressive cerebral/cerebellar atrophy. Breath-holding spells cause significant morbidity, are poorly understood, and have very limited treatment options.

Bainbridge-Ropers Syndrome in a Texan Boy: A Case Report and Review of the Literature.

Bainbridge-Ropers syndrome (BRPS) or additional sex combs-like 3 (ASXL3)-related disorder is a neurodevelopmental disorder caused by a de novo missense mutation in the ASXL3 gene found on chromosome 18. The number of BRPS cases recorded to date is less than 100. In this report, a six-year-old Texan boy with global developmental delay, aggressive behavior, insomnia, microcephaly, strabismus, facial dysmorphic features, vesicoureteral reflux (VUR), bilateral congenital renal dysplasia, gastroesophageal reflux disease (GERD), hypotonia, failure to thrive, dysphagia, and status post-gastrostomy tube was referred to Children's Health in Dallas for evaluation. The patient shares a chromosomal abnormality with his father that did not explain his clinical findings. Therefore, further tests were indicated and a whole-exome gene sequencing revealed a de novo pathogenic heterozygous mutation in the ASXL3 gene in chromosome 18q12.1 associated with autosomal dominant BRPS. To our knowledge, this is the first case of BRPS with bilateral congenital renal dysplasia and may be correlated to the presence of the ASXL3 gene in renal tissue. This discovery provides significant new information about this condition that might be essential for comprehending it.

Case report : a novel ASXL3 gene variant in a Sudanese boy.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. CASE PRESENTATION: The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for "psychomotor retardation" for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. CONCLUSION: Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature.

Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes. Bohring-Opitz syndrome (BOPS) was first described as a clinical syndrome and later found to be associated with pathogenic variants in ASXL1. This syndrome is characterized by developmental delay, microcephaly, characteristic facies, hypotonia, and feeding difficulties. Subsequently, pathogenic variants in ASXL2 were found to lead to Shashi-Pena syndrome (SHAPNS) and in ASXL3 to lead to Bainbridge-Ropers syndrome (BRPS). While SHAPNS and BRPS share many core features with BOPS, there also seem to be emerging clear differences. Here, we present five cases of BOPS, one case of SHAPNS, and four cases of BRPS. By adding our cohort to the limited number of previously published patients, we review the overlapping features of ASXL-related diseases that bind them together, while focusing on the characteristics that make each neurodevelopmental syndrome unique. This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families.

Further expanding the clinical phenotype in Bainbridge-Ropers syndrome and dissecting genotype-phenotype correlation in the ASXL3 mutational cluster regions.

Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, intellectual disability with poor or absent speech, feeding difficulties, growth failure, specific craniofacial and minor skeletal features. It was firstly reported in 2013 by Bainbridge et al., who observed a group of individuals sharing overlapping features with Bohring-Opitz syndrome which were caused by pathogenic variant in ASXL1, who indeed carried truncating mutations in ASXL3. To date, 33 cases were described in the literature. BRPS is caused by loss-of-function mutations in ASXL3 which are mostly located in two mutational cluster regions (MCR). The exact molecular mechanism of these mutations resulting in the disease phenotype is still uncertain due to the observation of LOF mutations in healthy population. Here, we report four individuals with BRPS carrying de novo LOF mutations in ASXL3, comparing and summarizing the clinical phenotype of all BRPS reported so far. Furthermore, we try to dissect the genotype-phenotype correlation among the two well reported MCRs in all BRPS from the literature.

ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making it difficult to develop both screenings and effective treatments. In this study, we examine a novel mechanistic insight in SCLC cells that could potentially provide a more sensitive therapeutic alternative for SCLC patients. METHODS: Biochemistry studies, including size exclusion chromatography, mass spectrometry, and western blot analysis, were conducted to determine the protein-protein interaction between additional sex combs-like protein 3 (ASXL3) and bromodomain-containing protein 4 (BRD4). Genomic studies, including chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and genome-wide analysis, were performed in both human and mouse SCLC cells to determine the dynamic relationship between BRD4/ASXL3/BAP1 epigenetic axis in chromatin binding and its effects on transcriptional activity. RESULTS: We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. Genetic depletion of ASXL3 results in a genome-wide reduction of histone H3K27Ac levels and BRD4-dependent gene expression in SCLC. Pharmacologically induced inhibition with BET-specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC that is characterized with high expression of ASXL3. CONCLUSIONS: Collectively, this study provides a mechanistic insight into the oncogenic function of BRD4/ASXL3/BAP1 epigenetic axis at active chromatin enhancers in SCLC-A subtype, as well as a potential new therapeutic option that could become more effective in treating SCLC patients with a biomarker of ASXL3-highly expressed SCLC cells.

Bainbridge-ropers syndrome caused by loss-of-function variants in ASXL3: Clinical abnormalities, medical imaging features, and gene variation in infancy of case report.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the Additional sex combs-like 3 (ASXL3) gene. Only four cases have been reported in China and are limited to the analysis of its clinical abnormalities, medical imaging features and gene variation. The aim of this study was to investigate the clinical phenotype, imaging manifestations and genetic characteristics of BPRS syndrome caused by ASXL3 gene mutation. Clinical data, medical imaging data and gene test results of BRPS in infant patients were retrospectively analyzed, and related literature was summarized. CASE PRESENTATION: At the age of 8 months, brain MRI showed that the subarachnoid space of the forehead was widened, part of the sulci was deepened, and the corpus callosum was thin. The development quotient (DQ) was determined using the 0~6-year-old pediatric examination table of neuropsychological development at 6 months and 8 months. The DQ of both tests was less than 69. Whole-exome sequencing revealed a heterozygous frameshift mutation c.3493_3494deTG in exon 12 of the ASXL3 gene, resulting in the amino acid change p. (Cys1165Ter). No variation was present at this site in her parents. Sanger sequencing of family members validated this analysis, suggesting a de novo mutation. The de novo ASXL3 mutations generated stop codons and were predicted, in silico, to generate a truncated ASXL3. CONCLUSIONS: The main clinical features of the patient included psychomotor development retardation, difficulty in feeding, hypotonia, and special facial features. MRI features showed that brain development lagged behind that of normal children. Genetic testing is helpful in the early diagnosis of BRPS.

Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.

The Additional sex combs-like (ASXL1-3) genes are linked to human neurodevelopmental disorders. The de novo truncating variants in ASXL1-3 proteins serve as the genetic basis for severe neurodevelopmental diseases such as Bohring-Opitz, Shashi-Pena, and Bainbridge-Ropers syndromes, respectively. The phenotypes of these syndromes are similar but not identical, and include dramatic craniofacial defects, microcephaly, developmental delay, and severe intellectual disability, with a loss of speech and language. Bainbridge-Ropers syndrome resulting from ASXL3 gene mutations also includes features of autism spectrum disorder. Human genomic studies also identified missense ASXL3 variants associated with autism spectrum disorder, but lacking more severe Bainbridge-Ropers syndromic features. While these findings strongly implicate ASXL3 in mammalian brain development, its functions are not clearly understood. ASXL3 protein is a component of the polycomb deubiquitinase complex that removes mono-ubiquitin from Histone H2A. Dynamic chromatin modifications play important roles in the specification of cell fates during early neural patterning and development. In this study, we utilize the frog, Xenopus laevis as a simpler and more accessible vertebrate neurodevelopmental model system to understand the embryological cause of Bainbridge-Ropers syndrome. We have found that ASXL3 protein knockdown during early embryo development highly perturbs neural cell fate specification, potentially resembling the Bainbridge-Ropers syndrome phenotype in humans. Thus, the frog embryo is a powerful tool for understanding the etiology of Bainbridge-Ropers syndrome in humans.

Novel mutation in the ASXL3 gene in a Chinese boy with microcephaly and speech impairment: A case report.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay. BRPS is caused by a heterozygous loss-of-function mutation in the ASXL3 gene. Due to limited knowledge of the disease and lack of specific features, clinical diagnosis of this syndrome is challenging. With the use of trio-based whole exome sequencing, we identified a novel ASXL3 mutation in a Chinese boy with BRPS and performed a literature review. CASE SUMMARY: A 3-year-old Chinese boy was referred to our hospital due to progressive postnatal microcephaly and intellectual disability with severe speech impairment for 2 years. His other remarkable clinical features were shown as follows: Facial dysmorphism, feeding difficulties, poor growth, motor delay, and abnormal behavior. For the proband, regular laboratory tests, blood tandem mass spectrometry, urine gas chromatographic mass spectrometry, karyotype, hearing screening, and brain magnetic resonance imaging were performed, with negative results. Therefore, for the proband and his unaffected parents, trio-based whole exome sequencing and subsequent validation by Sanger sequencing were performed. A novel nonsense variant in exon 11 of the ASXL3 gene (c.1795G>T; p.E599*) was detected, present in the patient but absent from his parents. Taking into account the concordant phenotypic features of our patient with reported BRPS patients and the detected truncated variant located in the known mutational cluster region, we confirmed a diagnosis of BRPS for this proband. The rehabilitation treatment seemed to have a mild effect. CONCLUSION: In this case, a novel nonsense mutation (c.1795G>T, p.E599*) in ASXL3 gene was identified in a Chinese boy with BRPS. This finding not only contributed to better genetic counseling and prenatal diagnosis for this family but also expanded the pathogenic mutation spectrum of ASXL3 gene and provided key information for clinical diagnosis of BRPS.

Chromosomal microarray and whole exome sequencing identify genetic causes of congenital hypothyroidism with extra-thyroidal congenital malformations.

BACKGROUND: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder. Although most patients present with isolated CH, some patients present with CH and extra-thyroidal congenital malformations (ECMs), for which less is known about the underlying genetics. The aim of this study was to investigate the genetic mechanisms in patients with CH and ECMs using chromosomal microarray (CMA) and whole exome sequencing (WES). METHODS: Peripheral venous blood samples were collected from 16 patients with CH and ECMs. Genomic DNA was extracted from peripheral blood leukocytes. CMA and WES were performed to detect copy number and single nucleotide variants. RESULTS: CMA identified clinically significant copy number variants in 7 patients consistent with their phenotypes. For 6 of them, the genotype and phenotype suggested a syndromic diagnosis, and the remaining patient carried a pathogenic microdeletion and microduplication including GLIS3. WES analysis identified 9 different variants in 7 additional patients. The variants included 2 known mutations (c.1096C>T (p.Arg366Trp) in KCNQ1 and c.848C>A (p.Pro283Gln) in NKX2-5) and 7 novel variants: one nonsense mutation (c.4330C>T (p.Arg1444*) in ASXL3), one frameshift mutation (c.1253_1259delACTCTGG (p.Asp418fs) in TG), three missense variants (c.1472C>T (p.Thr491Ile) in TG, c.4604A>G (p.Asp1535Gly) in TG, and c.2139G>T (p.Glu713Asp) in DUOX2, and two splice site variants (c.944-1G>C and c.3693 + 1G>T) in DUOX2. CONCLUSIONS: We report the first genetic study of CH patients with ECMs using CMA and WES. Overall, our detection rate for pathogenic and possibly pathogenic variants was 87.5% (14/16). We report 7 novel variants, expanding the mutational spectrum of TG, DUOX2, and ASXL3.

Mild prominence of the Sylvian fissure in a Bainbridge-Ropers syndrome patient with a novel frameshift variant in ASXL3.

A Japanese boy aged 7 years with Bainbridge-Ropers syndrome (BRPS) had a prominent domed forehead without metric ridge, mild prominence of the Sylvian fissure with bitemporal hollowing, and a heterozygous de novo novel variant "p.P1010Lfs*14" in ASXL3 gene in addition to typical findings of BRPS.

Whole exome sequencing diagnoses the first fetal case of Bainbridge-Ropers syndrome presenting as pontocerebellar hypoplasia type 1.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene. CASE: We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases. DISCUSSION: The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.