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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
Eur J Med Genet ; 64(4): 104182, 2021 Apr.
Article En | MEDLINE | ID: mdl-33639314

Disruption of the initiation of DNA replication is significantly associated with Meier-Gorlin syndrome (MGORS), an autosomal recessive condition of reduced growth, microtia and patellar a/hypoplasia. Biallelic mutations in CDC45, a member of the pre-initiation complex in DNA replication, cause a spectrum of phenotypes ranging from MGORS with craniosynostosis, through to isolated short stature and craniosynostosis. Here we report two affected sibs with MGORS and craniosynostosis, with biallelic variants in CDC45 identified by 10X Chromium whole genome sequencing. One variant is a frameshift mutation, predicted to be pathogenic, and is inherited in trans with a synonymous variant in a non-canonical exon (exon 7) of CDC45. An in vitro splicing assay showed that while the canonical CDC45 exon 6-exon 8 transcript (with skipping of exon 7; numbering as per NM001178010.2) remained as the predominant transcript, the variant allele induced the use of novel splice acceptor sites in intron 6, all of which produced transcripts harbouring premature stop codons. This perturbation of canonical splicing provides evidence that this synonymous variant is indeed a deleterious alteration in this family. This report adds to the initial patient cohort in which several synonymous variants were also described, further highlighting the contribution of this variant type in CDC45. It also reiterates the true potential pathogenicity of synonymous variants, which is a mutation type that is commonly ignored in variant prioritization strategies.

Cell Cycle Proteins/genetics , Congenital Microtia/genetics , Craniosynostoses/genetics , Growth Disorders/genetics , Micrognathism/genetics , Mutation , Patella/abnormalities , RNA Splice Sites , Cell Cycle Proteins/metabolism , Cells, Cultured , Child , Child, Preschool , Congenital Microtia/pathology , Craniosynostoses/pathology , Exons , Growth Disorders/pathology , Humans , Male , Micrognathism/pathology , Patella/pathology , Pedigree
Nat Commun ; 12(1): 833, 2021 02 05.
Article En | MEDLINE | ID: mdl-33547280

The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

Developmental Disabilities/genetics , Gene Expression Regulation, Developmental , Microcephaly/genetics , Micrognathism/genetics , Peptide Initiation Factors/genetics , RNA-Binding Proteins/genetics , Adolescent , Amino Acid Sequence , Animals , Child , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Embryo, Nonmammalian , Female , Humans , Lysine/analogs & derivatives , Lysine/genetics , Lysine/metabolism , Male , Microcephaly/metabolism , Microcephaly/pathology , Micrognathism/metabolism , Micrognathism/pathology , Peptide Initiation Factors/deficiency , Peptides/genetics , Peptides/metabolism , Protein Biosynthesis , Protein Conformation , Protein Isoforms/deficiency , Protein Isoforms/genetics , Ribosomes/genetics , Ribosomes/metabolism , Saccharomyces cerevisiae/drug effects , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Sequence Alignment , Sequence Homology, Amino Acid , Spermidine/pharmacology , Zebrafish , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism
Am J Med Genet A ; 185(4): 1317-1320, 2021 04.
Article En | MEDLINE | ID: mdl-33372358

A Sri Lankan male child with supraorbital hyperostosis, broad nasal bridge, small mandible, severe kyphoscoliosis, distal joint contractures of the hands and long second and third toes is described. A hemizygous pathogenic variant in exon 22 of the filamin A (FLNA) gene [NM_001110556.1: c.3557C>T; which leads to a nonsynonymous substitution of serine by leucine at codon 1186 in the FLNA protein; NP_001104026.1: p.Ser1186Leu] was identified. The clinical features observed in this patient were consistent with the cardinal manifestations seen in frontometaphyseal dysplasia 1 (FMD1). However, characteristic extra skeletal manifestations such as cardiac defects, uropathy, and hearing impairment which have previously been reported in association with this condition were absent in this patient.

Bone Diseases, Developmental/genetics , Filamins/genetics , Forehead/abnormalities , Genetic Predisposition to Disease , Osteochondrodysplasias/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Bone Diseases, Developmental/pathology , Child , Exons/genetics , Forehead/pathology , Humans , Male , Micrognathism/genetics , Micrognathism/pathology , Mutation, Missense/genetics , Osteochondrodysplasias/pathology , Phenotype , Sri Lanka/epidemiology
Am J Med Genet C Semin Med Genet ; 184(3): 644-655, 2020 09.
Article En | MEDLINE | ID: mdl-32888375

Mosaic genetic mutations may be somatic, germline, or "gonosomal" and have the potential to cause genetic syndromes, disorders, or malformations. Mutations can occur at any point in embryonic development and the timing determines the extent of distribution of the mutation throughout the body and different tissue types. The eye and visual pathway offer a unique opportunity to study somatic and gonosomal mosaic mutations as the eye consists of tissues derived from all three germ layers allowing disease pathology to be assessed with noninvasive imaging. In this review, we describe systemic and ocular manifestations in a child with mosaic Coffin-Siris syndrome. The patient presented with a significant medical history of accommodative esotropia and hyperopia, macrocephaly, polydactyly, global developmental delay, hypotonia, ureteropelvic junction (UPJ) obstruction, and brain MRI abnormalities. The ophthalmic findings in this patient were nonspecific, however, they are consistent with ocular manifestations reported in other patients with Coffin-Siris syndrome. We also review ophthalmic findings of select mosaic chromosomal and single-gene disorders. Ophthalmic assessment alongside clinical genetic testing may play an important role in diagnosis of genetic syndromes as well as understanding disease pathology, particularly when mosaicism plays a role.

Abnormalities, Multiple/genetics , Brain/diagnostic imaging , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Transcription Factors/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Brain/abnormalities , Child , Child, Preschool , Face/diagnostic imaging , Face/pathology , Female , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/pathology , Humans , Infant , Intellectual Disability/diagnostic imaging , Intellectual Disability/pathology , Male , Micrognathism/diagnostic imaging , Micrognathism/pathology , Mosaicism , Mutation/genetics , Neck/diagnostic imaging , Neck/pathology , Nuclear Proteins/genetics , Phenotype
Am J Med Genet A ; 182(9): 2058-2067, 2020 09.
Article En | MEDLINE | ID: mdl-32686290

SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin-Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin-Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement.

Abnormalities, Multiple/genetics , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Genetic Predisposition to Disease , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Nuclear Proteins/genetics , Transcription Factors/genetics , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/pathology , Adolescent , Child , Child, Preschool , Chromosomal Proteins, Non-Histone/genetics , Codon, Nonsense/genetics , Face/pathology , Female , Genetic Association Studies , Hand Deformities, Congenital/epidemiology , Hand Deformities, Congenital/pathology , Humans , Infant , Intellectual Disability/epidemiology , Intellectual Disability/pathology , Male , Micrognathism/epidemiology , Micrognathism/pathology , Neck/pathology , Phenotype
Clin Genet ; 98(2): 147-154, 2020 08.
Article En | MEDLINE | ID: mdl-32385905

Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.

Charcot-Marie-Tooth Disease/genetics , Cleidocranial Dysplasia/genetics , Ectodermal Dysplasia/genetics , Flavoproteins/genetics , Genetic Predisposition to Disease , Limb Deformities, Congenital/genetics , Micrognathism/genetics , Phosphoric Monoester Hydrolases/genetics , Age of Onset , Charcot-Marie-Tooth Disease/complications , Charcot-Marie-Tooth Disease/pathology , Child , Child, Preschool , Cleidocranial Dysplasia/complications , Cleidocranial Dysplasia/pathology , Dystonia/complications , Dystonia/genetics , Dystonia/pathology , Ectodermal Dysplasia/complications , Ectodermal Dysplasia/pathology , Female , Genotype , Humans , Limb Deformities, Congenital/complications , Limb Deformities, Congenital/pathology , Male , Micrognathism/complications , Micrognathism/pathology , Muscle Hypotonia/complications , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Mutation/genetics , Pedigree , Phenotype
Ann Clin Lab Sci ; 50(1): 140-145, 2020 Jan.
Article En | MEDLINE | ID: mdl-32161024

Coffin-Siris Syndrome (CSS) is a rare neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplastic digits/nails, and hypertrichosis. The genes causative of CSS mainly encode the SWI/SNF complex, which contributes to chromatin remodeling and regulates the access of transcriptional factors to specific gene sites. While ARID1B mutations account for a third of all CSS cases, the condition's phenotypic features vary widely. We document the case of a girl with CSS who presented with a variant facial appearance, global developmental delay with speech impairment, agenesis of the corpus callosum, funnel chest, and bilateral renal stones without hypertrichosis or hypoplasia of the fifth fingernail. Genetic analysis revealed that the patient had a novel heterozygous frameshift mutation c.2201dupG (p.Ser736Ilefs*27) on the ARID1B gene.

Abnormalities, Multiple/etiology , DNA-Binding Proteins/genetics , Face/abnormalities , Frameshift Mutation , Hand Deformities, Congenital/etiology , Intellectual Disability/etiology , Micrognathism/etiology , Neck/abnormalities , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Face/pathology , Female , Hand Deformities, Congenital/pathology , Humans , Infant , Intellectual Disability/pathology , Male , Micrognathism/pathology , Neck/pathology , Prognosis , Republic of Korea
Clin Genet ; 97(4): 672-674, 2020 04.
Article En | MEDLINE | ID: mdl-31994175

We describe the second patient with the de novo p.Arg377Trp variant in ACTL6A (Actin-like 6A) (MIM#604958) and a phenotype reminiscent a disorder of the BRG1-associated factor (BAF) complex, including dysmorphic facies and acral malformations. So far, only three patients with ACTL6A variants and neurodevelopmental delay have been reported but the specific p.Arg377Trp mutation seems to correlate with a distinctive phenotype well-fitting a BAFopathy, which lacks in individuals carrying different mutations. This could suggest an emergent genotype-phenotype correlation among the ACTL6A-related phenotype.

Abnormalities, Multiple/genetics , Actins/genetics , Chromosomal Proteins, Non-Histone/genetics , DNA-Binding Proteins/genetics , Hand Deformities, Congenital/genetics , Neurodevelopmental Disorders/genetics , Abnormalities, Multiple/pathology , Child , Hand Deformities, Congenital/pathology , Humans , Male , Micrognathism/pathology , Neurodevelopmental Disorders/pathology
Eur J Med Genet ; 63(3): 103739, 2020 Mar.
Article En | MEDLINE | ID: mdl-31421289

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.

Abnormalities, Multiple/genetics , DNA-Binding Proteins/genetics , Face/abnormalities , Foot Deformities, Congenital/genetics , Hand Deformities, Congenital/genetics , Hypotrichosis/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Transcription Factors/genetics , Twins, Monozygotic/genetics , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/pathology , Abnormalities, Multiple/physiopathology , Face/diagnostic imaging , Face/pathology , Face/physiopathology , Facies , Foot Deformities, Congenital/diagnostic imaging , Foot Deformities, Congenital/pathology , Foot Deformities, Congenital/physiopathology , Hand Deformities, Congenital/diagnostic imaging , Hand Deformities, Congenital/pathology , Hand Deformities, Congenital/physiopathology , Humans , Hypotrichosis/diagnostic imaging , Hypotrichosis/pathology , Hypotrichosis/physiopathology , Intellectual Disability/diagnostic imaging , Intellectual Disability/pathology , Intellectual Disability/physiopathology , Male , Micrognathism/diagnostic imaging , Micrognathism/pathology , Micrognathism/physiopathology , Mutation, Missense , Neck/diagnostic imaging , Neck/pathology , Neck/physiopathology , Phenotype , RNA Splicing , Sequence Deletion
J Hum Genet ; 64(9): 875-883, 2019 Sep.
Article En | MEDLINE | ID: mdl-31273320

Micrognathia is a common craniofacial deformity which represents hypoplastic development of the mandible, accompanied by retrognathia and consequent airway problems. Usually, micrognathia is accompanied by multiple systematic defects, known as syndromic micrognathia, and is in close association with genetic factors. Now, large quantities of pathogenic genes of syndromic micrognathia have been revealed. However, how these different pathogenic genes could lead to similar phenotypes, and whether there are some common characteristics among these pathogenic genes are still unknown. In this study, we proposed a genetic-phenotypic classification of syndromic micrognathia based on pathogenic genes information obtained from Phenolyzer, DAVID, OMIM, and PubMed database. Pathogenic genes of syndromic micrognathia could be divided into four groups based on gene function, including cellular processes and structures, cell metabolism, cartilage and bone development, and neuromuscular function. In addition, these four groups exhibited various clinical characteristics, and the affected systems, such as central nervous system, skeletal system, cardiovascular system, oral and dental system, respiratory system and muscle, were different in these four groups. This classification could provide meaningful insights into the pathogenesis of syndromic micrognathia, and offer some clues for understanding the molecular mechanism, as well as guiding precise clinical diagnosis and treatment for syndromic micrognathia.

Mandible/pathology , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Phenotype , Humans , Syndrome
Article En | MEDLINE | ID: mdl-31160358

Coffin-Siris syndrome (CSS) is a developmental disability, caused by genomic variants in the gene SMARCA4, in addition to other known genes, but the full spectrum of SMARCA4 variants that can cause CSS is unknown with 40% of cases not having molecular confirmation. In this report, we identify a patient with CSS, a severe cardiac phenotype, and a novel SMARCA4 variant. There is no experimental structure of human SMARCA4, so we use molecular modeling techniques to generate a structural model of human SMARCA4. We then map known SMARCA4 variants causative of CSS and our novel variant to the model. We use the resulting information to support the interpretation that the novel variant is causative of disease in our patient. Modeling demonstrates that the variant found in our patient is in a region of SMARCA4 associated with DNA binding, as are the other known pathogenic SMARCA4 variants mapped. Because of this structural information, we discuss how these variants may be disease-causing through a dominant negative effect of disrupting DNA binding.

Abnormalities, Multiple/genetics , DNA Helicases/genetics , Face/abnormalities , Hand Deformities, Congenital/genetics , Heart Diseases/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Models, Molecular , Neck/abnormalities , Nuclear Proteins/genetics , Transcription Factors/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Face/pathology , Hand Deformities, Congenital/diagnosis , Hand Deformities, Congenital/pathology , Heart Diseases/congenital , Heart Diseases/diagnosis , Heart Diseases/pathology , Humans , Infant, Newborn , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Male , Micrognathism/diagnosis , Micrognathism/pathology , Mutation , Neck/pathology
Mol Genet Genomic Med ; 7(6): e682, 2019 06.
Article En | MEDLINE | ID: mdl-30973214

BACKGROUND: Coffin-Siris syndrome (CSS) is characterized by intellectual disability, dysmorphic facial features, growth deficiency, microcephaly, and abnormalities of the fifth fingers/toes. CSS is caused by mutations in several genes of the BRG1-associated factor pathway including SMARCA4. METHODS: Whole-exome sequencing was performed on a 14-year-old female individual who presented with mild intellectual disability and dysmorphic features, tooth abnormalities, and short stature. She had brachydactyly but no aplasia or hypoplasia of the distal phalanx or nail of the fifth digit. She was also found to have retinal dystrophy that has not been previously reported in CSS. RESULTS: The individual presented herein was found to harbor a previously unreported de novo variant in SMARCA4. CONCLUSION: This case expands the phenotypic spectrum of CSS manifestations.

Abnormalities, Multiple/genetics , DNA Helicases/genetics , Face/abnormalities , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Nuclear Proteins/genetics , Retina/pathology , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Adolescent , Face/pathology , Female , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Micrognathism/pathology , Mutation, Missense , Neck/pathology , Phenotype
Prenat Diagn ; 39(2): 107-115, 2019 01.
Article En | MEDLINE | ID: mdl-30328631

OBJECTIVE: To investigate the intraobserver and interobserver reproducibility of a novel sonographic parameter named facial maxillary angle (FMA) and to establish nomograms of FMA, inferior facial angle (IFA), frontal nasal-mental angle (FNMA), maxilla-nasion-mandible angle (MNMA), and fetal profile line (FPL) in Chinese fetuses. METHODS: In this prospective cross-sectional study, FMA, IFA, FNMA, MNMA, and FPL were measured in 592 normal fetuses between 16 and 36 gestational weeks. FMA was measured twice by the same and another operator with a blinded method on the first 50 cases. The reference interval was defined as ±2SD. The efficacy of five sonographic markers was tested in 10 fetuses with micrognathia retrieved from the database of our unit. RESULTS: The intraclass correlation coefficient (95% CI) of intraobserver and interobserver reproducibility of FMA was 0.937 (0.890-0.964) and 0.891 (0.809-0.938), respectively. FMA, FNMA, and IFA increased slightly from 16 weeks till 28-31 weeks and decreased minimally thereafter. FMA and FNMA made correct diagnosis in all affected fetuses; MNMA and IFA identified nine and eight cases respectively, and FPL only detected five cases. CONCLUSION: A fixed cutoff of 66° for FMA and 136° for FNMA may be adopted as simple screening criteria of micrognathia.

Face/diagnostic imaging , Fetus/diagnostic imaging , Pregnancy Trimester, Second , Pregnancy Trimester, Third , Ultrasonography, Prenatal/methods , Adult , Cephalometry/methods , Cross-Sectional Studies , Face/embryology , Female , Gestational Age , Humans , Mandible/diagnostic imaging , Maxilla/diagnostic imaging , Micrognathism/diagnosis , Micrognathism/pathology , Nose/diagnostic imaging , Pregnancy , Reproducibility of Results
Eur J Med Genet ; 62(1): 27-34, 2019 Jan.
Article En | MEDLINE | ID: mdl-29698805

In the last 3 years de novo sequence variants in the ARID2 (AT-rich interaction domain 2) gene, a subunit of the SWI/SNF complex, have been linked to intellectual disabilities in 3 case reports including one which describes frameshift mutations in ARID2 in 2 patients with features resembling Coffin-Siris syndrome. Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by intellectual deficit, coarse facial features and hypoplastic or absent fifth fingernails and/or toenails among other features. Mutations in a number of different genes encoding SWI/SNF chromatin remodelling complex proteins have been described but the underlying molecular cause remains unknown in approximately 40% of patients with CSS. Here we describe 7 unrelated individuals, 2 with deletions of the ARID2 region and 5 with de novo truncating mutations in the ARID2 gene. Similarities to CSS are evident. Although hypertrichosis and hypoplasia of the fifth finger nail and distal phalanx do not appear to be common in these patients, toenail hypoplasia and the presence of Wormian bones might support the involvement of ARID2.

Abnormalities, Multiple/genetics , Face/abnormalities , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Micrognathism/genetics , Neck/abnormalities , Phenotype , Transcription Factors/genetics , Abnormalities, Multiple/pathology , Adolescent , Child , Child, Preschool , Face/pathology , Female , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Male , Micrognathism/pathology , Neck/pathology
Sci Adv ; 4(11): eaau0731, 2018 11.
Article En | MEDLINE | ID: mdl-30417093

Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration-approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.

Gene Expression Regulation/drug effects , Imidazoles/pharmacology , Intellectual Disability/drug therapy , KRIT1 Protein/physiology , Kruppel-Like Transcription Factors/metabolism , MAP Kinase Kinase Kinase 3/metabolism , Microfilament Proteins/physiology , Micrognathism/drug therapy , Pyridazines/pharmacology , Ribs/abnormalities , Animals , Cells, Cultured , Disease Progression , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Intellectual Disability/metabolism , Intellectual Disability/pathology , Kruppel-Like Transcription Factors/genetics , MAP Kinase Kinase Kinase 3/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Micrognathism/metabolism , Micrognathism/pathology , Mutation , Protein Kinase Inhibitors/pharmacology , Ribs/metabolism , Ribs/pathology , Signal Transduction , Zebrafish
Dental Press J Orthod ; 23(5): 19-23, 2018.
Article En | MEDLINE | ID: mdl-30427490

In order to lead to insights and discussion on proper use of Orthodontics and Pathology-related terminology, particularly in cases of smaller-than-usual maxilla and mandible - that is, anomalous ones -, this study compared the conceptual meaning of the term "atresia." It is considered improper when referring to maxilla and mandible with deficient growth compared to development that is satisfactory enough to reach normal size. To identify smaller maxilla and mandible, the most proper and accurate term is hypoplastic maxilla or mandible. This is because "atresia" stands for an anomaly related to lumen blockage in hollow organs, which is not the case for neither maxilla nor mandible. Hypoplastic maxilla or mandible can be properly and specifically referred to as micrognathia.

Mandible/abnormalities , Maxilla/abnormalities , Adolescent , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Male , Mandible/embryology , Mandible/growth & development , Maxilla/embryology , Maxilla/growth & development , Micrognathism/pathology , Terminology as Topic , Young Adult
Am J Med Genet A ; 176(11): 2250-2258, 2018 11.
Article En | MEDLINE | ID: mdl-30276971

Coffin-Siris syndrome (CSS; MIM 135900) is a multisystem congenital anomaly syndrome caused by mutations in the genes in the Brg-1 associated factors (BAF) complex. Classically, individuals with CSS have been described with hypo- or aplasia of the fifth digit nails or phalanges (hence the term "fifth digit syndrome"). Other physical features seen include growth restriction, coarse facial features, hypertrichosis or hirsutism, sparse scalp hair, dental anomalies, and other organ-system abnormalities. Varying degrees of developmental and intellectual delay are universal. To date, approximately 200 individuals have been described in the literature. With the advent of large-scale genetic testing such as whole-exome sequencing is becoming more available, more individuals are being found to have mutations in this pathway, and the phenotypic spectrum appears to be broadening. We report here a large cohort of 81 individuals with the diagnosis of CSS from the first parent-reported CSS/BAF complex registry in an effort to describe this variation among individuals, the natural history of the syndrome, and draw some gene-phenotype correlations. We propose that changes in the BAF complex may represent a spectrum of disorders, including both ARID1B-related nonsyndromic intellectual disability (ARID1B-ID) and CSS with classic physical features. In addition, we offer surveillance and management recommendations based on the medical issues encountered in this cohort to help guide physicians and patients' families.

Abnormalities, Multiple/pathology , Abnormalities, Multiple/therapy , Face/abnormalities , Hand Deformities, Congenital/pathology , Hand Deformities, Congenital/therapy , Intellectual Disability/pathology , Intellectual Disability/therapy , Micrognathism/pathology , Micrognathism/therapy , Neck/abnormalities , Parents , Registries , Abnormalities, Multiple/genetics , Child, Preschool , Cohort Studies , Face/pathology , Foot/pathology , Genetic Association Studies , Hand/pathology , Hand Deformities, Congenital/genetics , Humans , Infant , Intellectual Disability/genetics , Micrognathism/genetics , Neck/pathology
Dental press j. orthod. (Impr.) ; 23(5): 19-23, Sept.-Oct. 2018. graf
Article En | LILACS | ID: biblio-975021

ABSTRACT In order to lead to insights and discussion on proper use of Orthodontics and Pathology-related terminology, particularly in cases of smaller-than-usual maxilla and mandible - that is, anomalous ones -, this study compared the conceptual meaning of the term "atresia." It is considered improper when referring to maxilla and mandible with deficient growth compared to development that is satisfactory enough to reach normal size. To identify smaller maxilla and mandible, the most proper and accurate term is hypoplastic maxilla or mandible. This is because "atresia" stands for an anomaly related to lumen blockage in hollow organs, which is not the case for neither maxilla nor mandible. Hypoplastic maxilla or mandible can be properly and specifically referred to as micrognathia.

RESUMO Para induzir reflexões e discussões sobre o uso adequado da nomenclatura em Ortodontia e Patologia, para os casos em que a maxila e a mandíbula apresentam-se pequenas ou menores do que o habitual, ou seja, anômalas, comparou-se o significado conceitual do termo "atrésica". Esse termo não é adequado quando aplicado à maxila e à mandíbula para identificar situações em que houve um desenvolvimento com crescimento insuficiente para se chegar ao tamanho normal. Para identificar maxila e mandíbula menores, é mais adequado e preciso o uso do termo maxila ou mandíbula hipoplásica. Isso porque atresia representa uma anomalia por obstrução da luz ou lume em órgãos ocos, o que não ocorre na maxila ou na mandíbula. Maxila ou mandíbula hipoplásica também podem ser chamadas, apropriada e especificamente, de micrognatia.

Humans , Male , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Mandible/abnormalities , Maxilla/abnormalities , Mandible/growth & development , Mandible/embryology , Maxilla/growth & development , Maxilla/embryology , Micrognathism/pathology , Terminology as Topic
Eur J Hum Genet ; 26(8): 1083-1093, 2018 08.
Article En | MEDLINE | ID: mdl-29706634

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.

Abnormalities, Multiple/genetics , Face/abnormalities , Germ-Line Mutation , Hand Deformities, Congenital/genetics , Intellectual Disability/genetics , Meningeal Neoplasms/genetics , Meningioma/genetics , Micrognathism/genetics , Neck/abnormalities , Neurilemmoma/genetics , SMARCB1 Protein/genetics , Abnormalities, Multiple/pathology , Face/pathology , Hand Deformities, Congenital/pathology , Humans , Intellectual Disability/pathology , Meningeal Neoplasms/pathology , Meningioma/pathology , Micrognathism/pathology , Neck/pathology , Neurilemmoma/pathology , Phenotype , Polymorphism, Single Nucleotide