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Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(12): 1211-1215, 2021 Dec 10.
Article Zh | MEDLINE | ID: mdl-34839509

OBJECTIVE: To explore the pathogenesis of two siblings (including a fetus) from a pedigree affected with Joubert syndrome. METHODS: Peripheral blood samples of the proband and his parents as well as amniotic fluid and abortion tissues of the fetus were collected. Part of the samples were used for the extraction of DNA, and whole exome sequencing (WES) was carried out to screen potential variants in the proband and his parents. Suspected variants were subjected to bioinformatics analysis with consideration of the clinical phenotype, and were verified by Sanger sequencing of the proband, fetus and their parents.The remainders were used for the extraction of RNA, and the mechanism of splicing variant was validated by reverse transcription-PCR (RT-PCR). RESULTS: WES showed that both patients have carried c.175C>T (p.R59X) and c.553+1G>A compound heterozygous variants of the TMEM237 gene. Among these, c.175C>T was a nonsense mutation inherited from the asymptomatic mother, while c.553+1G>A was an alternative splicing mutation inherited from the asymptomatic father. RT-PCR showed that this variant has resulted in aberrant splicing by exon skipping. CONCLUSION: The compound heterozygous variants of the TMEM237 gene probably underlay the etiology of Joubert syndrome in this pedigree. Above finding has enriched the phenotype and variant spectrum of the TMEM237 gene, and facilitated genetic counseling and prenatal diagnosis for the family.

Abnormalities, Multiple , Eye Abnormalities , Kidney Diseases, Cystic , Abnormalities, Multiple/genetics , Cerebellum/abnormalities , Female , Genotype , Humans , Mutation , Pedigree , Phenotype , Pregnancy , Retina/abnormalities
Hum Genet ; 140(12): 1775-1789, 2021 Dec.
Article En | MEDLINE | ID: mdl-34642815

Missense variants located in the N-terminal region of WDR37 were recently identified to cause a multisystemic syndrome affecting neurological, ocular, gastrointestinal, genitourinary, and cardiac development. WDR37 encodes a WD40 repeat-containing protein of unknown function. We identified three novel WDR37 variants, two likely pathogenic de novo alleles and one inherited variant of uncertain significance, in individuals with phenotypes overlapping those previously reported but clustering in a different region of the protein. The novel alleles are C-terminal to the prior variants and located either within the second WD40 motif (c.659A>G p.(Asp220Gly)) or in a disordered protein region connecting the second and third WD40 motifs (c.778G>A p.(Asp260Asn) and c.770C>A p.(Pro257His)). The three novel mutants showed normal cellular localization but lower expression levels in comparison to wild-type WDR37. To investigate the normal interactions of WDR37, we performed co-immunoprecipitation and yeast two-hybrid assays. This revealed the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells. Next, we analyzed previously reported and novel mutants for their ability to dimerize with wild-type WDR37 and bind PACS proteins. Interaction with wild-type WDR37 was not affected for any variant; however, one novel mutant, p.(Asp220Gly), lost its ability to bind PACS1 and PACS2. In summary, this study presents a novel region of WDR37 involved in human disease, identifies PACS1 and PACS2 as major binding partners of WDR37 and provides insight into the functional effects of various WDR37 variants.

Abnormalities, Multiple/genetics , Mutant Proteins/genetics , Nuclear Proteins/genetics , Abnormalities, Multiple/metabolism , Adolescent , Animals , Cells, Cultured , Child , Child, Preschool , Cognitive Dysfunction/genetics , Female , Humans , Male , Mutant Proteins/metabolism , Nuclear Proteins/metabolism , Pedigree , Protein Binding , Syndrome , Two-Hybrid System Techniques , Vesicular Transport Proteins/metabolism
FASEB J ; 35(11): e21955, 2021 11.
Article En | MEDLINE | ID: mdl-34613626

Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.

Abnormalities, Multiple/metabolism , Cell Differentiation/genetics , DNA-Binding Proteins/metabolism , Face/abnormalities , Hematologic Diseases/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Muscle Cells/metabolism , Muscle Fibers, Skeletal/metabolism , Myeloid-Lymphoid Leukemia Protein/metabolism , Neoplasm Proteins/metabolism , Signal Transduction/genetics , Vestibular Diseases/metabolism , Abnormalities, Multiple/genetics , Adolescent , Animals , Child , Child, Preschool , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Hematologic Diseases/genetics , Histone-Lysine N-Methyltransferase/genetics , Humans , Infant , Male , Mice , Mice, Transgenic , Muscle Cells/pathology , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Neoplasm Proteins/genetics , Neuromuscular Junction/genetics , Neuromuscular Junction/metabolism , Vestibular Diseases/genetics
Hum Genet ; 140(12): 1709-1731, 2021 Dec.
Article En | MEDLINE | ID: mdl-34652576

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Facial Paralysis/genetics , Fibrosis/genetics , Mutation , Ophthalmoplegia/genetics , Peripheral Nervous System Diseases/genetics , Tubulin/genetics , Abnormalities, Multiple/genetics , Adolescent , Adult , Amino Acid Substitution , Arginine , Child , Child, Preschool , Facial Paralysis/diagnosis , Facial Paralysis/physiopathology , Female , Fibrosis/diagnosis , Fibrosis/physiopathology , Histidine , Humans , Infant , Male , Ophthalmoplegia/diagnosis , Ophthalmoplegia/physiopathology , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Syndrome , Young Adult
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 841-844, 2021 Sep 10.
Article Zh | MEDLINE | ID: mdl-34487526

OBJECTIVE: To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis. METHODS: Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing. RESULTS: Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife. CONCLUSION: The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.

Abnormalities, Multiple , Eye Abnormalities , Kidney Diseases, Cystic , Abnormalities, Multiple/genetics , Cerebellum/abnormalities , Cerebellum/diagnostic imaging , Eye Abnormalities/genetics , Female , Fetus , Humans , Mutation , Phenotype , Pregnancy , Retina/abnormalities
Article En | MEDLINE | ID: mdl-34501546

Aim: Aim of this case report is to describe oro-facial abnormalities in a patient affected by Helsmoortel-Van der Aa syndrome, a rare autism syndrome, with not well described dental and cranial malformations. Case Report: Helsmoortel-Van der Aa Syndrome is a rare autosomal genetic syndrome causing mental impairment and autism, craniofacial dysmorphism, chest deformity and multiple organs dysfunction. Oro-facial involvement in Helsmoortel-Van der Aa syndrome has not been thoroughly described yet. The present article reports a case of a 9 years old male patient affected by Helsmoortel-Van der Aa Syndrome, presenting with oral breathing typical facies, high arched palate, II class and dental crowding. The patient teething was adequate to his age. The enamel of incisors and molars showed demineralization areas and dark spots, a clinical picture consistent with molar incisor hypomineralization syndrome. These hypo-mineralized areas are more susceptible to cavities, in fact the patient's 4.6 tooth was decayed. The child was brought to our attention due to a mucocele on the lower lip, confirmed by histopathologic examination. Available data on oro-dental manifestation of this syndrome are rather poor and inconsistent, also due to the rarity of the disease. The finding of enamel abnormalities in the presented case could suggest a potential genetic etiopathogenesis linked to the same genes causing Helsmoortel-Van der Aa syndrome.

Abnormalities, Multiple , Autistic Disorder , Intellectual Disability , Abnormalities, Multiple/genetics , Child , Humans , Male , Mutation , Phenotype
N Engl J Med ; 385(14): 1292-1301, 2021 09 30.
Article En | MEDLINE | ID: mdl-34587386

BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS: We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).

Abnormalities, Multiple/genetics , Congenital Abnormalities/genetics , Genetic Pleiotropy , Intracellular Signaling Peptides and Proteins/genetics , Mutation , Receptors, G-Protein-Coupled/genetics , Wnt Proteins/metabolism , Animals , Disease Models, Animal , Fibroblasts/metabolism , Gene Knock-In Techniques , Genes, Recessive , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Transgenic , Pedigree , Phenotype , Receptors, G-Protein-Coupled/metabolism , Syndrome , Wnt Signaling Pathway
Hum Genet ; 140(10): 1403-1416, 2021 Oct.
Article En | MEDLINE | ID: mdl-34368901

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37-70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4-100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time.Prospero registration CRD42019094101.

Abnormalities, Multiple/genetics , Genome, Human , Nervous System Diseases/genetics , Whole Exome Sequencing , Genetic Variation , Humans , Sequence Analysis, Protein
Int J Mol Sci ; 22(15)2021 Jul 27.
Article En | MEDLINE | ID: mdl-34360805

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.

Abnormalities, Multiple , Casein Kinase I , Cleft Palate , Exophthalmos , Extracellular Matrix Proteins , Genetic Variation , Microcephaly , Osteosclerosis , Phenotype , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/mortality , Abnormalities, Multiple/pathology , Casein Kinase I/genetics , Casein Kinase I/metabolism , Cleft Palate/genetics , Cleft Palate/metabolism , Cleft Palate/mortality , Cleft Palate/pathology , Exophthalmos/genetics , Exophthalmos/metabolism , Exophthalmos/mortality , Exophthalmos/pathology , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Humans , Microcephaly/genetics , Microcephaly/metabolism , Microcephaly/mortality , Microcephaly/pathology , Osteosclerosis/genetics , Osteosclerosis/metabolism , Osteosclerosis/mortality , Osteosclerosis/pathology
Development ; 148(16)2021 08 15.
Article En | MEDLINE | ID: mdl-34351428

Neocortical progenitor cells generate subtypes of excitatory projection neurons in sequential order followed by the generation of astrocytes. The transcription factor zinc finger and BTB domain-containing protein 20 (ZBTB20) has been implicated in regulation of cell specification during neocortical development. Here, we show that ZBTB20 instructs the generation of a subset of callosal projections neurons in cortical layers II/III in mouse. Conditional deletion of Zbtb20 in cortical progenitors, and to a lesser degree in differentiating neurons, leads to an increase in the number of layer IV neurons at the expense of layer II/III neurons. Astrogliogenesis is also affected in the mutants with an increase in the number of a specific subset of astrocytes expressing GFAP. Astrogliogenesis is more severely disrupted by a ZBTB20 protein containing dominant mutations linked to Primrose syndrome, suggesting that ZBTB20 acts in concert with other ZBTB proteins that were also affected by the dominant-negative protein to instruct astrogliogenesis. Overall, our data suggest that ZBTB20 acts both in progenitors and in postmitotic cells to regulate cell fate specification in the mammalian neocortex.

Astrocytes/metabolism , Neocortex/growth & development , Neurogenesis/genetics , Neurons/metabolism , Transcription Factors/metabolism , Abnormalities, Multiple/genetics , Animals , Calcinosis/genetics , Ear Diseases/genetics , Female , Gene Knockout Techniques , Intellectual Disability/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscular Atrophy/genetics , Mutation, Missense , Neocortex/metabolism , Signal Transduction/genetics , Stem Cells/metabolism , Transcription Factors/genetics
Nat Commun ; 12(1): 5013, 2021 08 18.
Article En | MEDLINE | ID: mdl-34408147

Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.

Abnormalities, Multiple/genetics , Bone Diseases, Developmental/genetics , Homeodomain Proteins/genetics , Limb Deformities, Congenital/genetics , Transcription Factors/genetics , Abnormalities, Multiple/embryology , Abnormalities, Multiple/metabolism , Animals , Bone Diseases, Developmental/embryology , Bone Diseases, Developmental/metabolism , Disease Models, Animal , Female , Gene Deletion , Homeodomain Proteins/metabolism , Humans , Limb Deformities, Congenital/embryology , Limb Deformities, Congenital/metabolism , Loss of Function Mutation , Male , Mice, Inbred C57BL , Multigene Family , Transcription Factors/metabolism
Medicine (Baltimore) ; 100(30): e26687, 2021 Jul 30.
Article En | MEDLINE | ID: mdl-34397695

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.

Heart Diseases/etiology , Malignant Hyperthermia/complications , Skin Abnormalities/complications , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Child, Preschool , Contracture/etiology , Ductus Arteriosus, Patent/etiology , Female , Heart Diseases/physiopathology , Humans , Malignant Hyperthermia/genetics , Malignant Hyperthermia/physiopathology , Saudi Arabia , Skin Abnormalities/genetics , Skin Abnormalities/physiopathology
Hum Genet ; 140(10): 1459-1469, 2021 Oct.
Article En | MEDLINE | ID: mdl-34436670

During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease.

Abnormalities, Multiple/genetics , Evolution, Molecular , Lung Diseases/genetics , Lung/abnormalities , Lung/growth & development , Lung/ultrastructure , Organogenesis/genetics , Adult , Cadaver , Female , Fetus , Genetic Variation , Genome, Human , Humans , Male , Pregnancy
Elife ; 102021 08 31.
Article En | MEDLINE | ID: mdl-34463256

Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

Abnormalities, Multiple/genetics , Epigenesis, Genetic/genetics , Face/abnormalities , Genetic Variation/genetics , Hematologic Diseases/genetics , Rubinstein-Taybi Syndrome/genetics , Transcriptome/genetics , Vestibular Diseases/genetics , Abnormalities, Multiple/metabolism , Animals , Chromatin/genetics , Disease Models, Animal , Female , Genetic Techniques , Hematologic Diseases/metabolism , Mice , Phenotype , Rubinstein-Taybi Syndrome/metabolism , Vestibular Diseases/metabolism
Taiwan J Obstet Gynecol ; 60(4): 775-777, 2021 Jul.
Article En | MEDLINE | ID: mdl-34247824

OBJECTIVE: We present partial monosomy 8p (8p23.2→pter) and partial trisomy 15q (15q21.2→qter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency (NT) and an abnormal maternal serum screening result. CASE REPORT: A 29-year-old primigravid woman underwent chorionic villus sampling (CVS) at 13 weeks of gestation because of an increased NT thickness of 3.2 mm at 12 weeks of gestation and an abnormal maternal serum screening for Down syndrome result with a calculated risk of 1/29. Her husband was 33 years old, and there was no family history of congenital malformations. CVS revealed a derived chromosome 8 or der(8). Cytogenetic analysis of the parents revealed a karyotype of 46,XY,t(8;15)(p21.3;q13) in the father and a karyotype of 46,XX in the mother. The CVS result was 46,XY,der(8)t(8;15)(p21.3;q13)pat. The woman requested for amniocentesis at 16 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a result of arr 8p23.3p23.2 (191,530-2,625,470) × 1.0, arr 15q21.2q26.3 (50,903,432-102,338,129) × 3.0 with a 2.434-Mb deletion of 8p23.3-p23.2 including DLGAP2, CLN8 and ARHGEF10, and a 51.435-Mb duplication of 15q21.2-q26.3 including CYP19A1 and IGF1R. Conventional cytogenetic analysis of cultured amniocytes revealed the result of 46,XY,der(8) t(8;15)(p23.2;q21.2)pat in the fetus. The pregnancy was subsequently terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism. CONCLUSION: Maternal serum screening and NT screening may incidentally detect familial unbalanced reciprocal translocations, and aCGH analysis is useful for a precise determination of the breakpoints of the translocation and the involvement of the related genes under such a circumstance.

Abnormalities, Multiple/diagnosis , Translocation, Genetic/genetics , Trisomy/diagnosis , Abnormalities, Multiple/embryology , Abnormalities, Multiple/genetics , Abortion, Eugenic , Adult , Chorionic Villi Sampling , Chromosome Deletion , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 8/genetics , Comparative Genomic Hybridization , Cytogenetic Analysis , Female , Humans , Incidental Findings , Male , Maternal Serum Screening Tests , Nuchal Translucency Measurement , Paternal Inheritance/genetics , Pregnancy , Trisomy/genetics
Clin Nephrol ; 96(4): 243-250, 2021 Oct.
Article En | MEDLINE | ID: mdl-34308837

The retinitis pigmentosa -GTPase regulator interacting protein 1-like gene (RPGRIP1L) encodes a ciliary protein essential for basic embryonic development. Biallelic variants of RPGRIP1L; cause Joubert syndrome (JS) with renal defects. In addition to characteristic JS features (cerebellar and brain stem malformations, developmental delays, hypotonia, irregular breathing patterns, eye movement abnormalities, ataxia, and intellectual disability), affected individuals typically also exhibit renal disorders, such as cystic kidney disease and nephronophthisis. Here, we describe a 10-year-old female of Chinese descent who was referred to hospital due to lower limb arthralgia. However, the presence of short stature, facial deformities, renal abnormalities, and renal failure suggested a diagnosis of congenital syndrome disorder. Whole-exome sequencing (WES) revealed that the patient was homozygous for a previously unreported RPGRIP1L variant featuring a missense mutation (NM_015272; c.2180G>A, p.Gly727Asp). A subsequent cranial MRI confirmed the presence of midbrain molar tooth sign and cerebellar Dandy-Walker malformation. However, no significant developmental delays or neurological abnormalities were noted. This study makes a significant contribution to the literature by expanding knowledge of the JS-causing RPGRIP1L variant spectrum, enhancing understanding of RPGRIP1L variant-associated JS phenotypes.

Abnormalities, Multiple , Eye Abnormalities , Kidney Diseases, Cystic , Abnormalities, Multiple/genetics , Adaptor Proteins, Signal Transducing/genetics , Cerebellum/abnormalities , Cerebellum/diagnostic imaging , Child , China , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Female , Humans , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Mutation, Missense , Pregnancy , Retina/abnormalities
Nat Commun ; 12(1): 4050, 2021 06 30.
Article En | MEDLINE | ID: mdl-34193871

The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

Abnormalities, Multiple/pathology , Carrier Proteins/metabolism , Craniofacial Abnormalities/pathology , DNA Damage , Hand Deformities, Congenital/pathology , Heredodegenerative Disorders, Nervous System/pathology , Intellectual Disability/pathology , Mutation , Nails, Malformed/pathology , Neural Stem Cells/pathology , Nuclear Proteins/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Carrier Proteins/genetics , Cells, Cultured , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/metabolism , Hand Deformities, Congenital/genetics , Hand Deformities, Congenital/metabolism , Heredodegenerative Disorders, Nervous System/genetics , Heredodegenerative Disorders, Nervous System/metabolism , Humans , Intellectual Disability/genetics , Intellectual Disability/metabolism , Nails, Malformed/genetics , Nails, Malformed/metabolism , Neural Stem Cells/metabolism , Nuclear Proteins/genetics , Organoids
Genes (Basel) ; 12(6)2021 06 19.
Article En | MEDLINE | ID: mdl-34205270

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.

Abnormalities, Multiple/genetics , Face/abnormalities , Genotype , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Phenotype , Abnormalities, Multiple/pathology , Face/pathology , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Micrognathism/pathology , Mutation , Neck/pathology , Transcription Factors/genetics
Genes (Basel) ; 12(6)2021 06 21.
Article En | MEDLINE | ID: mdl-34205586

Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive-compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome.

Abnormalities, Multiple/genetics , Adaptor Proteins, Vesicular Transport/genetics , Cerebellum/abnormalities , Ciliopathies/genetics , Eye Abnormalities/genetics , Kidney Diseases, Cystic/genetics , Phenotype , Retina/abnormalities , Abnormalities, Multiple/pathology , Adolescent , Cerebellum/pathology , Ciliopathies/pathology , Eye Abnormalities/pathology , Homozygote , Humans , Kidney Diseases, Cystic/pathology , Male , Mutation, Missense , Retina/pathology
Hum Genet ; 140(9): 1395-1401, 2021 Sep.
Article En | MEDLINE | ID: mdl-34313816

The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery.

Abnormalities, Multiple/genetics , DNA Damage , Genes, Recessive , Homozygote , Tumor Suppressor Proteins/deficiency , Abnormalities, Multiple/pathology , Child , Humans , Male