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International Journal of Oral and... Jul 2022Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding...
Patients with mandibular hypoplasia and upper airway obstruction are at an increased risk of feeding and swallowing difficulties. Little has been described regarding these outcomes following mandibular distraction. The aim of this study was to evaluate the effect of mandibular distraction on feeding and swallowing function. A retrospective study was performed on 22 patients with non-isolated mandibular hypoplasia and severe upper airway obstruction treated with mandibular distraction. Median age at first mandibular distraction was 3.1 years (interquartile range 2.3-6.0 years) and the median follow-up time was 3.5 years (interquartile range 2.0-9.4 years). Prior to mandibular distraction, feeding difficulties were present in 18 patients. Swallowing difficulties were present in 20 patients, all of whom had problems in the oral phase of swallowing, while 11 patients had additional problems in the pharyngeal phase. Following mandibular distraction, at the time of follow-up, feeding difficulties persisted in 13 patients. Swallowing difficulties in the oral phase remained present in all 20 patients, while pharyngeal phase problems persisted in seven patients. In conclusion, feeding and swallowing difficulties are highly prevalent in non-isolated patients and often persist following mandibular distraction. Moreover, these can be the reason that decannulation cannot be accomplished. Hence, awareness and close follow-up by a specialized speech therapist is of paramount importance.
Topics: Airway Obstruction; Child; Child, Preschool; Deglutition; Humans; Infant; Mandible; Micrognathism; Osteogenesis, Distraction; Retrospective Studies; Treatment Outcome
PubMed: 34952774
DOI: 10.1016/j.ijom.2021.11.015 -
European Journal of Medical Genetics Feb 2022The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to...
The ARID1A gene is an infrequent cause of Coffin-Siris syndrome (CSS) and has been associated with severe to profound developmental delays and hypotonia in addition to characteristic craniofacial and digital findings. We present three fetuses and a male neonate with ventriculomegaly/hydrocephalus, absence of the corpus callosum (ACC), cerebellar hypoplasia, retinal dysplasia, lung lobulation defects, renal dysplasia, imperforate or anteriorly placed anus, thymus hypoplasia and a single umbilical artery. Facial anomalies included downslanting palpebral fissures, wide-spaced eyes, low-set and posteriorly rotated ears, a small jaw, widely spaced nipples and hypoplastic nails. All fetuses had heterozygous variants predicting premature protein truncation in ARID1A (c.4886dup:p.Val1630Cysfs*18; c.4860dup:p.Pro1621Thrfs*27; and c.175G>T:p.Glu59*) and the baby's microarray demonstrated mosaicism for a deletion at chromosome 1p36.11 (arr[GRCh37] 1p36.11(26,797,508_27,052,080)×1∼2), that contained the first exon of ARID1A. Although malformations, in particular ACC, have been described with CSS caused by pathogenic variants in ARID1A, prenatal presentations associated with this gene are rare. Retinal dysplasia, lung lobulation defects and absent thymus were novel findings in association with ARID1A variants. Studies in cancer have demonstrated that pathogenic ARID1A variants hamper nuclear import of the protein and/or affect interaction with the subunits of SWI/SNF complex, resulting in dysregulation of the PI3K/AKT pathway and perturbed PTEN and PIKC3A signaling. As haploinsufficiency for PTEN and PIKC3A can be associated with ventriculomegaly/hydrocephalus, aberrant expression of these genes is a putative mechanism for the brain malformations demonstrated in patients with ARID1A variants.
Topics: Abnormalities, Multiple; Aborted Fetus; Adult; DNA-Binding Proteins; Face; Female; Hand Deformities, Congenital; Humans; Intellectual Disability; Micrognathism; Mutation; Neck; Phenotype; Pregnancy; Prenatal Diagnosis; Transcription Factors
PubMed: 34942405
DOI: 10.1016/j.ejmg.2021.104407 -
Genetics in Medicine : Official Journal... Feb 2022BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead...
PURPOSE
BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.
METHODS
We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes.
RESULTS
We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1.
CONCLUSION
We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.
Topics: Abnormalities, Multiple; Actins; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Exome; Hand Deformities, Congenital; Humans; Micrognathism; Retrospective Studies
PubMed: 34906496
DOI: 10.1016/j.gim.2021.09.017 -
BMC Pregnancy and Childbirth Nov 2021Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants...
BACKGROUND
Auriculocondylar syndrome (ACS) is a rare disorder characterized by micrognathia, mandibular condyle hypoplasia, and auricular abnormalities. Only 6 pathogenic variants of GNAI3 have been identified associated with ACS so far. Here, we report a case of prenatal genetic diagnosis of ACS carrying a novel GNAI3 variant.
CASE PRESENTATION
A woman with 30 weeks of gestation was referred to genetic counseling for polyhydramnios and fetal craniofacial anomaly. Severe micrognathia and mandibular hypoplasia were identified on ultrasonography. The mandibular length was 2.4 cm, which was markedly smaller than the 95th percentile. The ears were low-set with no cleft or notching between the lobe and helix. The face was round with prominent cheeks. Whole-exome sequencing identified a novel de novo missense variant of c.140G > A in the GNAI3 gene. This mutation caused an amino acid substitution of p.Ser47Asn in the highly conserved G1 motif, which was predicted to impair the guanine nucleotide-binding function. All ACS cases with GNAI3 mutations were literature reviewed, revealing female-dominated severe cases and right-side-prone deformities.
CONCLUSION
Severe micrognathia and mandibular hypoplasia accompanied by polyhydramnios are prenatal indicators of ACS. We expanded the mutation spectrum of GNAI3 and summarized clinical features to promote awareness of ACS.
Topics: Adult; Ear; Ear Diseases; Female; Fetal Diseases; GTP-Binding Protein alpha Subunits, G12-G13; Humans; Micrognathism; Mutation, Missense; Phenotype; Polyhydramnios; Pregnancy; Prenatal Diagnosis
PubMed: 34789173
DOI: 10.1186/s12884-021-04238-x -
BMC Medical Genomics Nov 2021Coffin-Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp...
Identification of de novo mutations for ARID1B haploinsufficiency associated with Coffin-Siris syndrome 1 in three Chinese families via array-CGH and whole exome sequencing.
BACKGROUND
Coffin-Siris syndrome (CSS) is a multiple malformation syndrome characterized by intellectual disability associated with coarse facial features, hirsutism, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. CSS represents a small group of intellectual disability, and could be caused by at least twelve genes. The genetic background is quite heterogenous, making it difficult for clinicians and genetic consultors to pinpoint the exact disease types.
METHODS
Array-Comparative Genomic Hybridization (array-CGH) and whole exome sequencing (WES) were applied for three trios affected with intellectual disability and clinical features similar with those of Coffin-Siris syndrome. Sanger sequencing was used to verify the detected single-nucleotide variants (SNVs).
RESULTS
All of the three cases were female with normal karyotypes of 46, XX, born of healthy, non-consanguineous parents. A 6q25 microdeletion (arr[hg19]6q25.3(155,966,487-158,803,979) × 1) (2.84 Mb) (case 1) and two loss-of-function (LoF) mutations of ARID1B [c.2332 + 1G > A in case 2 and c.4741C > T (p.Q1581X) in case 3] were identified. All of the three pathogenic abnormalities were de novo, not inherited from their parents. After comparison of publicly available microdeletions containing ARID1B, four types of microdeletions leading to insufficient production of ARID1B were identified, namely deletions covering the whole region of ARID1B, deletions covering the promoter region, deletions covering the termination region or deletions covering enhancer regions.
CONCLUSION
Here we identified de novo ARID1B mutations in three Chinese trios. Four types of microdeletions covering ARID1B were identified. This study broadens current knowledge of ARID1B mutations for clinicians and genetic consultors.
Topics: Abnormalities, Multiple; Chromosomes, Human, Pair 6; Comparative Genomic Hybridization; DNA-Binding Proteins; Face; Female; Hand Deformities, Congenital; Haploinsufficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Micrognathism; Neck; Point Mutation; Polymorphism, Single Nucleotide; Sequence Deletion; Transcription Factors; Exome Sequencing
PubMed: 34775996
DOI: 10.1186/s12920-021-01119-2 -
BMC Medical Genomics Oct 2021The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate-dependent chromatin-remodeling complex associated with the regulation of DNA...
BACKGROUND
The switch/sucrose nonfermenting (SWI/SNF) complex is an adenosine triphosphate-dependent chromatin-remodeling complex associated with the regulation of DNA accessibility. Germline mutations in the components of the SWI/SNF complex are related to human developmental disorders, including the Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. These disorders are collectively referred to as SWI/SNF complex-related intellectual disability disorders (SSRIDDs).
METHODS
Whole-exome sequencing was performed in 564 Korean patients with neurodevelopmental disorders. Twelve patients with SSRIDDs (2.1%) were identified and their medical records were retrospectively analyzed.
RESULTS
ARID1B, found in eight patients, was the most frequently altered gene. Four patients harbored pathogenic variants in SMARCA4, SMARCB1, ARID2, and SMARCA2. Ten patients were diagnosed with CSS, and one patient without a typical phenotype was diagnosed with ARID1B-related nonsyndromic intellectual disability. Another patient harboring the SMARCA2 pathogenic variant was diagnosed with NCBRS. All pathogenic variants in ARID1B were truncating, whereas variants in SMARCA2, SMARCB1, and SMARCA4 were nontruncating (missense). Frequently observed phenotypes were thick eyebrows (10/12), hypertrichosis (8/12), coarse face (8/12), thick lips (8/12), and long eyelashes (8/12). Developmental delay was observed in all patients, and profound speech delay was also characteristic. Agenesis or hypoplasia of the corpus callosum was observed in half of the patients (6/12).
CONCLUSIONS
SSRIDDs have a broad disease spectrum, including NCBRS, CSS, and ARID1B-related nonsyndromic intellectual disability. Thus, SSRIDDs should be considered as a small but important cause of human developmental disorders.
Topics: Abnormalities, Multiple; Face; Facies; Female; Foot Deformities, Congenital; Genotype; Hand Deformities, Congenital; Humans; Hypotrichosis; Infant; Infant, Newborn; Intellectual Disability; Male; Micrognathism; Neck; Phenotype; Republic of Korea
PubMed: 34706719
DOI: 10.1186/s12920-021-01104-9 -
European Journal of Dentistry Oct 2021Previous studies showed that noggin gene () sequence alterations, as well as epigenetic factors, could influence mandibular development. The aim of this study was to...
OBJECTIVES
Previous studies showed that noggin gene () sequence alterations, as well as epigenetic factors, could influence mandibular development. The aim of this study was to analyze clinical characteristics, gene sequences, and promoter methylation sites in patients with mandibular micrognathism.
MATERIALS AND METHODS
A total of 35 individuals of five Colombian families were subject to clinical and cephalometric analysis for mandibular micrognathism. One nonaffected individual of each family was included as a control. DNA was isolated from whole blood sample from all individuals by salting out method. Nine gene fragments were amplified by polymerase chain reaction (PCR) and sequenced. Identification of CpG islands for methylation analysis at the gene promoter was performed by MSP-PCR kit (Qiagen R).
STATISTICAL ANALYSIS
A descriptive statistical analysis was carried out evaluating the presence or absence of genetics variants and the methylation sites in the NOG gene.
RESULTS
sequence results of affected individuals with mandibular micrognathism for one of the families studied demonstrated that they were heterozygous for 672 C/A (new mutation). For a second family, individuals were heterozygous for 567 G/C (single nucleotide polymorphism [SNP] RS116716909). For DNA analyzed from all patients studied, no methylations were observed at the gene promoter region.
CONCLUSION
Our results suggested that 672 C/A and 567 G/C variants could be involved in the presence of mandibular micrognathism. Moreover, lack of methylation sites at the gene promoter region of all individuals studied suggests possibly other epigenetic factors could modulate mandibular growth. The search of genetic variants related with mandibular micrognathism will allow to predict in an integral way the development patterns of the patients and therefore establish a better clinical treatment.
PubMed: 34592770
DOI: 10.1055/s-0041-1726162 -
The Iowa Orthopaedic Journal 2021Coffin-Siris Syndrome (CSS) is a rare, genetic syndrome characterized by multiple anomalies, including scoliosis. However, there are only a few reports about the... (Review)
Review
Coffin-Siris Syndrome (CSS) is a rare, genetic syndrome characterized by multiple anomalies, including scoliosis. However, there are only a few reports about the management of scoliosis in these patients. We present the case of an 8-year-old female with CSS presenting with a progressive, rigid thoracolumbar kyphoscoliosis. She was successfully treated with a magnetically controlled growing rod, demonstrating improved ambulatory capacity and performance of activities of daily living. In pediatric patients with Coffin-Siris syndrome, magnetic expandable rods can be considered as an option for the management of progressive early-onset scoliosis. V.
Topics: Abnormalities, Multiple; Activities of Daily Living; Child; Face; Female; Hand Deformities, Congenital; Humans; Intellectual Disability; Micrognathism; Neck; Scoliosis
PubMed: 34552404
DOI: No ID Found -
Journal of Medical Genetics Aug 2022Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication...
INTRODUCTION
Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS).
OBJECTIVE
Identification of novel genes associated with MGORS.
METHODS
Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, structural protein analysis and modelling in budding yeast.
RESULTS
A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with -related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia.
CONCLUSION
is a new disease-associated gene, expanding the genetic aetiology of MGORS.
Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Congenital Microtia; Craniosynostoses; Growth Disorders; Humans; Micrognathism; Patella; Saccharomyces cerevisiae
PubMed: 34353863
DOI: 10.1136/jmedgenet-2020-107572 -
Genes Jun 2021Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ...
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 , , , , , , , , , and . 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 -related variants are thought to have more learning and developmental struggles, and individuals with -related variants, while they also have developmental delay, tend to have more severe organ-related complications. -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.
Topics: Abnormalities, Multiple; Face; Genotype; Hand Deformities, Congenital; Humans; Intellectual Disability; Micrognathism; Mutation; Neck; Phenotype; Transcription Factors
PubMed: 34205270
DOI: 10.3390/genes12060937