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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
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
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
Sci Rep ; 11(1): 12175, 2021 06 09.
Article En | MEDLINE | ID: mdl-34108542

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.

Abnormalities, Multiple/pathology , Craniofacial Abnormalities/pathology , Face/pathology , Imaging, Three-Dimensional/methods , Models, Statistical , Muscular Atrophy/pathology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Anthropometry , Case-Control Studies , Child , Child, Preschool , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/metabolism , Face/abnormalities , Female , Follow-Up Studies , Growth Charts , Humans , Infant , Male , Middle Aged , Muscular Atrophy/genetics , Muscular Atrophy/metabolism , Phenotype , Prognosis , Young Adult
PLoS Genet ; 17(6): e1009603, 2021 06.
Article En | MEDLINE | ID: mdl-34143769

The inability to maintain a strictly regulated endo(lyso)somal acidic pH through the proton-pumping action of the vacuolar-ATPases (v-ATPases) has been associated with various human diseases including heritable connective tissue disorders. Autosomal recessive (AR) cutis laxa (CL) type 2C syndrome is associated with genetic defects in the ATP6V1E1 gene and is characterized by skin wrinkles or loose redundant skin folds with pleiotropic systemic manifestations. The underlying pathological mechanisms leading to the clinical presentations remain largely unknown. Here, we show that loss of atp6v1e1b in zebrafish leads to early mortality, associated with craniofacial dysmorphisms, vascular anomalies, cardiac dysfunction, N-glycosylation defects, hypotonia, and epidermal structural defects. These features are reminiscent of the phenotypic manifestations in ARCL type 2C patients. Our data demonstrates that loss of atp6v1e1b alters endo(lyso)somal protein levels, and interferes with non-canonical v-ATPase pathways in vivo. In order to gain further insights into the processes affected by loss of atp6v1e1b, we performed an untargeted analysis of the transcriptome, metabolome, and lipidome in early atp6v1e1b-deficient larvae. We report multiple affected pathways including but not limited to oxidative phosphorylation, sphingolipid, fatty acid, and energy metabolism together with profound defects on mitochondrial respiration. Taken together, our results identify complex pathobiological effects due to loss of atp6v1e1b in vivo.

Abnormalities, Multiple/genetics , Cutis Laxa/genetics , Epithelial Cells/metabolism , Skin/metabolism , Vacuolar Proton-Translocating ATPases/genetics , Zebrafish Proteins/genetics , Abnormalities, Multiple/metabolism , Abnormalities, Multiple/pathology , Animals , Cutis Laxa/metabolism , Cutis Laxa/pathology , Disease Models, Animal , Endosomes/metabolism , Endosomes/pathology , Epithelial Cells/pathology , Gene Expression Regulation , Humans , Larva/genetics , Larva/growth & development , Larva/metabolism , Lipidomics , Longevity/genetics , Lysosomes/metabolism , Lysosomes/pathology , Metabolome/genetics , Mitochondria/metabolism , Mitochondria/pathology , Oxidative Phosphorylation , Protein Isoforms/deficiency , Protein Isoforms/genetics , Skin/pathology , Syndrome , Transcriptome , Vacuolar Proton-Translocating ATPases/deficiency , Zebrafish/embryology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/deficiency
Am J Hum Genet ; 108(6): 1053-1068, 2021 06 03.
Article En | MEDLINE | ID: mdl-33909990

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Abnormalities, Multiple/pathology , Adenosine Triphosphatases/genetics , Craniofacial Abnormalities/pathology , DNA Methylation , Epigenesis, Genetic , Growth Disorders/pathology , Heart Septal Defects, Ventricular/pathology , Mutation , Neurodevelopmental Disorders/pathology , Phenotype , Abnormalities, Multiple/genetics , Case-Control Studies , Cohort Studies , Craniofacial Abnormalities/genetics , Female , Genetic Predisposition to Disease , Growth Disorders/genetics , Heart Septal Defects, Ventricular/genetics , Humans , Infant, Newborn , Male , Neurodevelopmental Disorders/genetics
Genes (Basel) ; 12(5)2021 04 28.
Article En | MEDLINE | ID: mdl-33925166

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

Abnormalities, Multiple/genetics , Agenesis of Corpus Callosum/genetics , Anus, Imperforate/genetics , Blepharophimosis/genetics , Blepharoptosis/genetics , Cholestasis/genetics , Cleft Palate/genetics , Constipation/genetics , Craniofacial Abnormalities/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Marfan Syndrome/genetics , Mediator Complex/genetics , Mental Retardation, X-Linked/genetics , Muscle Hypotonia/congenital , Retinitis Pigmentosa/genetics , Abnormalities, Multiple/pathology , Agenesis of Corpus Callosum/pathology , Anus, Imperforate/pathology , Blepharophimosis/pathology , Blepharoptosis/pathology , Cholestasis/pathology , Cleft Palate/pathology , Constipation/pathology , Craniofacial Abnormalities/pathology , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/pathology , Marfan Syndrome/pathology , Mental Retardation, X-Linked/pathology , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Phenotype , Retinitis Pigmentosa/pathology
Genes (Basel) ; 12(4)2021 03 25.
Article En | MEDLINE | ID: mdl-33805950

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

Abnormalities, Multiple/pathology , DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/pathology , Histone Demethylases/genetics , Mutation , Neoplasm Proteins/genetics , Phenotype , Vestibular Diseases/pathology , Abnormalities, Multiple/genetics , Face/pathology , Hematologic Diseases/genetics , Humans , Vestibular Diseases/genetics
Genes (Basel) ; 12(4)2021 04 05.
Article En | MEDLINE | ID: mdl-33916386

Spondylocarpotarsal synostosis syndrome (SCT) is characterized by vertebral fusions, a disproportionately short stature, and synostosis of carpal and tarsal bones. Pathogenic variants in FLNB, MYH3, and possibly in RFLNA, have been reported to be responsible for this condition. Here, we present two unrelated individuals presenting with features typical of SCT in which Sanger sequencing combined with whole genome sequencing identified novel, homozygous intragenic deletions in FLNB (c.1346-1372_1941+389del and c.3127-353_4223-1836del). Both deletions remove several consecutive exons and are predicted to result in a frameshift. To our knowledge, this is the first time that large structural variants in FLNB have been reported in SCT, and thus our findings add to the classes of variation that can lead to this disorder. These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT.

Abnormalities, Multiple/etiology , Filamins/genetics , Gene Deletion , Lumbar Vertebrae/abnormalities , Musculoskeletal Diseases/etiology , Mutation , Scoliosis/congenital , Synostosis/etiology , Thoracic Vertebrae/abnormalities , Abnormalities, Multiple/pathology , Adult , Child , Female , Humans , Lumbar Vertebrae/pathology , Male , Musculoskeletal Diseases/pathology , Pedigree , Scoliosis/etiology , Scoliosis/pathology , Syndrome , Synostosis/pathology , Thoracic Vertebrae/pathology
Eur J Med Genet ; 64(6): 104210, 2021 Jun.
Article En | MEDLINE | ID: mdl-33794347

Kabuki syndrome (KS) is a genetic disorder caused by pathogenic variants in KMT2D or KDM6A, and manifesting with multi-systemic involvement, including recognizable facial features, developmental delay and multiple congenital anomalies. Ophthalmological involvement has been described in varying rates in several studies. We aimed to evaluate the prevalence and nature of ophthalmological findings in a cohort of KS patients in Israel. Medical records of all patients diagnosed with KS in our tertiary center between 2004 and 2020 were retrospectively reviewed. Data collected included physical examination findings, molecular analysis as well as comprehensive ophthalmic characteristics including visual acuity, ocular alignment and motility, ocular adnexa, anterior segments and dilated fundus exams. Finally, an updated systematic review of the literature was performed. Thirteen unrelated patients were included in the study, diagnosed at an age raging from the first months of life to 20 years. Of these, three (23%) showed significant ophthalmological abnormalities, beyond the characteristic structural findings of long palpebral fissures and lower eyelid eversion. These included bilateral posterior colobomata in the first patient; bilateral ptosis, hypermetropia, esotropia, blue sclera and anisocoria in the second; and bilateral congenital cataracts in the third. To conclude, our findings underscore the importance of a comprehensive ophthalmological evaluation as part of the routine multidisciplinary assessment of children suspected/diagnosed with KS.

Abnormalities, Multiple/pathology , Eye Abnormalities/pathology , Face/abnormalities , Hematologic Diseases/pathology , Vestibular Diseases/pathology , Abnormalities, Multiple/genetics , Adolescent , Child , Child, Preschool , DNA-Binding Proteins/genetics , Eye Abnormalities/genetics , Face/pathology , Hematologic Diseases/genetics , Histone Demethylases/genetics , Humans , Infant , Neoplasm Proteins/genetics , Vestibular Diseases/genetics , Visual Acuity
Eur J Med Genet ; 64(6): 104212, 2021 Jun.
Article En | MEDLINE | ID: mdl-33794348

BACKGROUD: Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, which resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease. However, it is not easy to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity. CASE REPORT: We report on a fetus who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 gestational weeks and confirmed by MRI examination. The pregnancy was terminated at 23 weeks of gestation. Postaxial polydactyly and deficiency in occipital bone and skin were identified in the induced fetus. RESULTS: The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome, including a 2-bp insertion, NM_023073.3:c.1383_1384dup; p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a complete function loss of the CPLANE1 gene. CONCLUSION: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome, which increases the clinical diagnosis difficulty, especially for prenatal diagnosis. Our findings provided a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of the CPLANE1 gene.

Abnormalities, Multiple/genetics , Aborted Fetus/abnormalities , Cerebellum/abnormalities , Eye Abnormalities/genetics , Kidney Diseases, Cystic/genetics , Membrane Proteins/genetics , Mutation , Retina/abnormalities , Abnormalities, Multiple/pathology , Adult , Cerebellum/diagnostic imaging , Cerebellum/pathology , Eye Abnormalities/pathology , Female , Humans , Kidney Diseases, Cystic/pathology , RNA Splicing , Retina/pathology , Ultrasonography, Prenatal
Eur J Med Genet ; 64(7): 104213, 2021 Jul.
Article En | MEDLINE | ID: mdl-33930582

Holt-Oram syndrome (HOS) is a rare, autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. A wide spectrum of TBX5 mutations have been reported previously, most resulting in a null allele leading to haploinsufficiency. TBX5 gene duplications have been previously reported in association with typical and atypical HOS phenotypes. Ulnar-Mammary syndrome (UMS) is a distinct rare, autosomal dominant condition caused by mutations in the TBX3 gene. TBX5 and TBX3 are physically linked in cis on human chromosome 12 and contiguous chromosome 12q24 deletions comprising both TBX5 and TBX3 genes have been previously reported but to our knowledge, duplications have never been described. We report on a large German family with at least 17 affected individuals over 6 generations bearing a duplication at 12q24.21 identified on array-CGH comprising both TBX5 and TBX3 genes. Affected patients are presenting with HOS and UMS symptoms, consisting of variable limb anomalies involving the radial and the ulnar rays and cardiac findings such as congenital heart defects, persistent arterial duct or aortic stenosis, and non-classical symptoms, such as supernumerary nipples and cardiomyopathy. Fluorescence in situ hybridisation confirmed a tandem duplication at the 12q24.21 locus. This is the first report of a contiguous TBX3/TBX5 duplication associated with HOS/UMS phenotype.

Abnormalities, Multiple/genetics , Breast Diseases/genetics , Heart Defects, Congenital/genetics , Heart Septal Defects, Atrial/genetics , Lower Extremity Deformities, Congenital/genetics , Phenotype , T-Box Domain Proteins/genetics , Ulna/abnormalities , Upper Extremity Deformities, Congenital/genetics , Abnormalities, Multiple/pathology , Breast Diseases/complications , Breast Diseases/pathology , Female , Gene Duplication , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Heart Septal Defects, Atrial/complications , Heart Septal Defects, Atrial/pathology , Humans , Lower Extremity Deformities, Congenital/complications , Lower Extremity Deformities, Congenital/pathology , Male , Pedigree , Ulna/pathology , Upper Extremity Deformities, Congenital/complications , Upper Extremity Deformities, Congenital/pathology
Mol Genet Genomics ; 296(4): 809-821, 2021 Jul.
Article En | MEDLINE | ID: mdl-33866394

Holt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.

Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Heart Septal Defects, Atrial/genetics , Heart Septal Defects, Atrial/pathology , Lower Extremity Deformities, Congenital/genetics , Lower Extremity Deformities, Congenital/pathology , T-Box Domain Proteins/genetics , Upper Extremity Deformities, Congenital/genetics , Upper Extremity Deformities, Congenital/pathology , Adult , Aged, 80 and over , Cells, Cultured , Cytogenetic Analysis , DNA Mutational Analysis , Genetic Association Studies , Genetic Heterogeneity , HEK293 Cells , Humans , Male , Mutation/physiology , Phenotype , T-Box Domain Proteins/physiology
Am J Med Genet A ; 185(6): 1691-1699, 2021 06.
Article En | MEDLINE | ID: mdl-33713555

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

Cleft Lip/genetics , Cleft Palate/genetics , Eye Abnormalities/genetics , Fingers/abnormalities , Knee Joint/abnormalities , Knee/abnormalities , Lower Extremity Deformities, Congenital/genetics , Protein-Serine-Threonine Kinases/genetics , Skin Abnormalities/genetics , Syndactyly/genetics , Urogenital Abnormalities/genetics , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Aborted Fetus/pathology , Cleft Lip/epidemiology , Cleft Lip/pathology , Cleft Palate/epidemiology , Cleft Palate/pathology , Exome/genetics , Eye Abnormalities/epidemiology , Eye Abnormalities/pathology , Female , Fingers/pathology , Genetic Predisposition to Disease , Homozygote , Humans , Infant, Newborn , Knee/pathology , Knee Joint/pathology , Lower Extremity Deformities, Congenital/epidemiology , Lower Extremity Deformities, Congenital/pathology , Mutation/genetics , Phosphorylation , Pregnancy , Skin Abnormalities/epidemiology , Skin Abnormalities/pathology , Syndactyly/epidemiology , Syndactyly/pathology , Urogenital Abnormalities/epidemiology , Urogenital Abnormalities/pathology
Am J Med Genet A ; 185(6): 1787-1793, 2021 06.
Article En | MEDLINE | ID: mdl-33749998

Few population-based studies have analyzed patterns of co-occurring birth defects among those with trisomy 13. We evaluated the frequency of all possible combinations of any one, two, three, or four additional co-occurring birth defects among 736 individuals with trisomy 13 using data from the Texas Birth Defects Registry for deliveries during 1999-2014. We calculated the observed-to-expected ratio for each combination, adjusting for the known tendency for birth defects to cluster non-specifically. To address potential ascertainment differences among live births and non-live births, we repeated analyses specifically among live births. The combination of defects with the largest observed-to-expected ratio was microcephalus, reduction deformities of brain (e.g., holoprosencephaly), anomalies of nose, and polydactyly. As expected, most of the highest 30 observed-to-expected ratios involved combinations with documented features of trisomy 13, including defects of the scalp (e.g., aplasia cutis) and heart. Results were similar among sensitivity analyses restricted to live births. Our findings may help further delineate the phenotypic spectrum for trisomy 13 and may inform future research related to improving screening and counseling for the condition.

Abnormalities, Multiple/genetics , Heart Defects, Congenital/genetics , Holoprosencephaly/genetics , Trisomy 13 Syndrome/genetics , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/pathology , Adolescent , Adult , Brain/pathology , Child , Child, Preschool , Congenital Abnormalities/epidemiology , Congenital Abnormalities/genetics , Congenital Abnormalities/pathology , Female , Genetic Counseling , Heart Defects, Congenital/pathology , Holoprosencephaly/pathology , Humans , Infant , Infant, Newborn , Live Birth/epidemiology , Live Birth/genetics , Male , Pregnancy , Texas , Trisomy 13 Syndrome/epidemiology , Trisomy 13 Syndrome/pathology , Young Adult
Am J Med Genet A ; 185(6): 1903-1907, 2021 06.
Article En | MEDLINE | ID: mdl-33750016

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

Abnormalities, Multiple/genetics , Bone Diseases, Developmental/genetics , Craniofacial Abnormalities/genetics , Dwarfism/genetics , Hyperostosis, Cortical, Congenital/genetics , Hypocalcemia/genetics , Receptors, Virus/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/diagnostic imaging , Bone Diseases, Developmental/pathology , Cardiovascular Abnormalities/diagnosis , Cardiovascular Abnormalities/genetics , Cardiovascular Abnormalities/pathology , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/diagnostic imaging , Craniofacial Abnormalities/pathology , Dwarfism/diagnosis , Dwarfism/diagnostic imaging , Dwarfism/pathology , Facial Bones/abnormalities , Facial Bones/pathology , Female , Fetus , Genetic Predisposition to Disease , Heterozygote , Humans , Hyperostosis, Cortical, Congenital/diagnosis , Hyperostosis, Cortical, Congenital/diagnostic imaging , Hyperostosis, Cortical, Congenital/pathology , Hypocalcemia/diagnosis , Hypocalcemia/diagnostic imaging , Hypocalcemia/pathology , Male , Mutation/genetics , Pregnancy , Skull/abnormalities , Skull/pathology , Spleen/abnormalities , Spleen/diagnostic imaging , Whole Exome Sequencing