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Genetics in Medicine : Official Journal... Oct 2023To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard...
PURPOSE
To evaluate whether deep prenatal phenotyping of fetal brain abnormalities (FBAs) increases diagnostic yield of trio-exome sequencing (ES) compared with standard phenotyping.
METHODS
Retrospective exploratory analysis of a multicenter prenatal ES study. Participants were eligible if an FBA was diagnosed and subsequently found to have a normal microarray. Deep phenotyping was defined as phenotype based on targeted ultrasound plus prenatal/postnatal magnetic resonance imaging, autopsy, and/or known phenotypes of other affected family members. Standard phenotyping was based on targeted ultrasound alone. FBAs were categorized by major brain findings on prenatal ultrasound. Cases with positive ES results were compared with those that have negative results by available phenotyping, as well as diagnosed FBAs.
RESULTS
A total of 76 trios with FBAs were identified, of which 25 (33%) cases had positive ES results and 51 (67%) had negative results. Individual modalities of deep phenotyping were not associated with diagnostic ES results. The most common FBAs identified were posterior fossa anomalies and midline defects. Neural tube defects were significantly associated with receipt of a negative ES result (0% vs 22%, P = .01).
CONCLUSION
Deep phenotyping was not associated with increased diagnostic yield of ES for FBA in this small cohort. Neural tube defects were associated with negative ES results.
Topics: Pregnancy; Female; Humans; Prenatal Diagnosis; Retrospective Studies; Exome Sequencing; Fetus; Brain Diseases; Brain; Neural Tube Defects; Ultrasonography, Prenatal
PubMed: 37326029
DOI: 10.1016/j.gim.2023.100915 -
Frontiers in Endocrinology 2024Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by agenesis/aplasia of the uterus and upper part of the vagina in females with... (Review)
Review
Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a congenital anomaly characterized by agenesis/aplasia of the uterus and upper part of the vagina in females with normal external genitalia and a normal female karyotype (46,XX). Patients typically present during adolescence with complaints of primary amenorrhea where the diagnosis is established with significant implications including absolute infertility. Most often cases appear isolated with no family history of MRKH syndrome or related anomalies. However, cumulative reports of familial recurrence suggest genetic factors to be involved. Early candidate gene studies had limited success in their search for genetic causes of MRKH syndrome. More recently, genomic investigations using chromosomal microarray and genome-wide sequencing have been successful in detecting promising genetic variants associated with MRKH syndrome, including 17q12 () and 16p11.2 () deletions and sequence variations in and , pointing towards a heterogeneous etiology with various genes involved. With uterus transplantation as an emerging fertility treatment in MRKH syndrome and increasing evidence for genetic etiologies, the need for genetic counseling concerning the recurrence risk in offspring will likely increase. This review presents the advancements in MRKH syndrome genetics from early familial occurrences and candidate gene searches to current genomic studies. Moreover, the review provides suggestions for future genetic investigations and discusses potential implications for clinical practice.
Topics: Humans; Mullerian Ducts; 46, XX Disorders of Sex Development; Congenital Abnormalities; Female
PubMed: 38699388
DOI: 10.3389/fendo.2024.1368990 -
Journal of Psychopathology and Clinical... Aug 2023Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with...
Sotos syndrome (Sotos) and Tatton-Brown-Rahman Syndrome (TBRS) are two of the most common overgrowth disorders associated with intellectual disability. Individuals with these syndromes tend to have similar cognitive profiles and high likelihood of autism symptomatology. However, whether and how sensory processing is affected is currently unknown. Parents/caregivers of 36 children with Sotos and 20 children with TBRS completed the Child Sensory Profile-2 (CSP-2) and the Sensory Behavior Questionnaire (SBQ) along with other standardized questionnaires assessing autistic traits (Social Responsiveness Scale, Second Edition, SRS-2), attention deficit hyperactivity disorder (ADHD) traits (Conners 3), anxiety (Spence Children's Anxiety Scale, Parent Version, SCAS-P), and adaptive behavior (Vineland Adaptive Behavior Scales Third Edition). Sensory processing differences were clearly evident in both syndromes, though there was significant variation in both cohorts. SBQ data indicated that both the and of sensory behavior were more severe when compared to neurotypicals, with levels of sensory behavior impact and frequency being similar to autistic children. CSP-2 data indicated 77% of children with Sotos and 85% children with TBRS displayed clear differences in sensory Registration (missing sensory input). Clear differences relating to Body Position (proprioceptive response to joint and muscle position; 79% Sotos; 90% TBRS) and Touch (somatosensory response to touch on skin; 56% Sotos; 60% TBRS) were also particularly prevalent. Correlation analyses demonstrated that in both syndromes sensory processing differences tend to be associated with difficulties relating to autistic traits, anxiety, and some domains of ADHD. In Sotos, sensory processing differences were also associated with lower adaptive behavior skills. This first detailed assessment of sensory processing, alongside other clinical features, in relatively large cohorts of children with Sotos and TBRS, demonstrates that sensory processing differences have a profound impact on everyday life. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Topics: Child; Humans; Intellectual Disability; Sotos Syndrome; Abnormalities, Multiple; Touch; Musculoskeletal Abnormalities; Touch Perception
PubMed: 37289542
DOI: 10.1037/abn0000837 -
Scientific Reports Aug 2023Urogenital congenital anomalies (UCAs) is defined as "any live-birth with a urinary or genital condition" and affects millions of men and women worldwide. However, sex...
Urogenital congenital anomalies (UCAs) is defined as "any live-birth with a urinary or genital condition" and affects millions of men and women worldwide. However, sex differences and related environmental risk factors in UCAs burden on a global scale have not been assessed. Using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we estimated prevalence, incidence, mortality and disability-adjusted life years (DALYs) of UCAs from 1990 to 2019 by sex, region, and socio-demographic Index (SDI) in 204 countries and territories. The disease burden of UCAs was also estimated attributable to each risk factor were estimated according to risk exposure. In 2019, UCAs caused 10,200 all-ages deaths (95% UI 7550-13,400). The combined global incidence rate was 8.38 per 1000 (95% UI 5.88-12.0) live births. The ASIR increased slightly, while the ASDR decreased from 1990 to 2019.The UCAs burden varies greatly depending on the development level and geographical location. The UCAs burden was significantly higher in men than in women, and the sex differences showed an enlarging trend. Health risks and issues, including pollution, child and maternal malnutrition, diet habits, unsafe sanitation and water source, were detected to be positively related to UCAs burden. Albeit the age-standardised prevalence, mortality, incidence, and DALYs of UCAs have decreased, they still cause a public health challenge worldwide. The high deaths and DALYs rates in low and low-middle SDI countries highlight the urgent need for improved preventive, diagnostic, and therapeutic measures. Global strategies for enhancing water safety, reducing pollution, and healthy diets are crucial steps in reducing the burden of UCAs.
Topics: Child; Pregnancy; Female; Humans; Male; Sex Characteristics; Urogenital Abnormalities; Risk Factors; Urinary Tract; Cost of Illness
PubMed: 37608070
DOI: 10.1038/s41598-023-40939-3 -
Epigenetics & Chromatin Dec 2023Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal...
BACKGROUND
Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal folate deficiency could impact the occurrence of NTDs, however, the mechanisms involved in the cause of NTDs are poorly defined.
RESULTS
Here, we report that histone H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) expression was significantly downregulated, and low levels of H3K79me2 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Using ChIP-seq assays, we found that a decrease of H3K79me2 downregulates the expression of Shh and Sufu in mouse embryonic stem cells (mESC) under folate deficiency. Interestingly, folate antagonist methotrexate treatment led to attenuation of H3K79me2 due to Dot1l, affecting Shh and Sufu genes regulation. Upon further analysis, we find that the genes Shh and Sufu are both downregulated in the brain tissues of mice and humans with NTDs. There was a positive correlation between the transcription levels of Shh, Sufu and the protein levels of DOT1L by Pearson correlation analysis.
CONCLUSION
Our results indicate that abnormal Shh and Sufu genes expression reduced by aberrant Dot1l-mediated H3K79me2 levels could be the cause of NTDs occurrence.
Topics: Mice; Humans; Animals; Histones; Neural Tube Defects; Methylation; Folic Acid; Gene Expression; Hedgehog Proteins; Histone-Lysine N-Methyltransferase
PubMed: 38093377
DOI: 10.1186/s13072-023-00517-3 -
Genes Jul 2023Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central... (Review)
Review
Split Hand-Foot Malformation (SHFM) is a congenital limb defect characterized by a median cleft of the hands and/or feet due to the absence/hypoplasia of the central rays. It may occur as part of a syndromic condition or as an isolated malformation. The most common of the six genetic loci identified for this condition is correlated to SHFM1 and maps in the 7q21q22 region. SHFM1 is characterized by autosomal dominant transmission, incomplete penetrance and variable expressivity. Associated features often include hearing loss, intellectual disability/developmental delay and craniofacial abnormalities. Disruption of the genes, mapping within the SHFM1 locus, is now known to be responsible for the phenotype. Through SNP array, we analyzed a patient affected by SHFM1 associated with deafness and an abnormality of the inner ear (incomplete partition type I); we identified a deletion in 7q21, not involving the /6 genes, but including exons 15 and 17 of , known to act as exonic enhancers (eExons) of the /6 genes. We further demonstrated the role of eExons in regulating /6 expression by means of showing a reduced expression of the /6 genes through RT-PCR in a patient-derived lymphoblastoid cell line. Furthermore, our data and a review of published cases do not support the hypothesis that /6 are imprinted in humans. This work is an example of how the disruption of regulatory elements can be responsible for congenital malformations.
Topics: Humans; Genes, Homeobox; Lower Extremity; Limb Deformities, Congenital; Deafness; Transcription Factors; Homeodomain Proteins
PubMed: 37628577
DOI: 10.3390/genes14081526 -
Scientific Reports Jul 2023Clubfoot is one of the common orthopaedic deformities. However, regardless of its' treatment high success rate, recurrence of the deformity is a serious issue. The aim...
Clubfoot is one of the common orthopaedic deformities. However, regardless of its' treatment high success rate, recurrence of the deformity is a serious issue. The aim of this study is to evaluate if radiographic angles can be used for clubfoot recurrence prediction. This is a prospective study on 91 patients (134 feet) with mean age of 9.5 ± 2.3 days and male/female ratio of 2/1 on patients with congenital clubfoot admitted to our hospital. Pre and one-year post-tenotomy tibiocalcaneal (TIC-L), talocalcaneal (TC-L) and calcaneal-first metatarsal angles (C1M-L) in the lateral view of the patients' radiographs, and their recurrence status until three years were measured. Ten feet experienced relapse. The mean pre and one-year follow-up measurements of TC-L, C1M-L, and TIC-L angles were significantly different between patients who experienced relapse and others (P < .05). The cut-off points of 1.75 and 6.5 for one-year follow-up Pirani and Dimeglio scores for recurrence prediction were suggested respectively. Also, cut-off points of 26.5 and 79.5 for one-year follow-up TC-L and TIC-L angles for recurrence prediction were calculated, respectively. We demonstrated that the pre-tenotomy and one-year follow-up TIC-L, TC-L, and C1M-L angles are helpful in clubfoot recurrence prediction after Ponseti treatment.
Topics: Humans; Male; Female; Infant; Child; Clubfoot; Prospective Studies; Casts, Surgical; Treatment Outcome; Tenotomy; Recurrence; Follow-Up Studies
PubMed: 37474789
DOI: 10.1038/s41598-023-38882-4 -
Clinical Oral Investigations Sep 2023Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction,...
OBJECTIVE
Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction, dysphagia among other previously described severe health complications. CZS is usually diagnosed postpartum by evident/apparent neural development problems. Although there are some reports of craniofacial/dentition development in CZS, several clinical oral aspects are still unknown. This study describes some structural and functional characteristics of facial and cranial growth and deciduous dentition in CZS-affected children.
MATERIAL AND METHODS
Some cranial, facial and dental characteristics were determined in 14 children with CZS aged 3-5 years and compared them against 12 apparently healthy children paired by age and gender.
RESULTS
Fourteen CZS cases presented microcephaly, maxillary prognathism, altered facial thirds, asymmetric pupillary line, bruxism (p = 0.006), deep and anterior open bite and distal step decidual molar relationship (p = 0.031). CZS children cannot feed by themselves and most cannot walk and have not develop coordinated and intelligible language according to their chronological age. In contrast, controls presented normal skull features, have autonomous locomotion skills, speak intelligible language, feed by themselves, presented a harmonic intermaxillary relationship and have symmetrical facial thirds.
CONCLUSION
Microcephaly, dysphagia, bruxism, mandibular retrognathia, altered facial proportions and malocclusion are the main craniofacial and oral features at CZS.
CLINICAL RELEVANCE
The complications of CZS including those related with the face and the oral cavity are still being identified. This study revealed some cranial, facial and oral features in children affected by CSZ. Interdisciplinary rehabilitation protocols must address these syndromic features that could improve children and parents living conditions.
Topics: Pregnancy; Female; Humans; Infant, Newborn; Child; Zika Virus Infection; Microcephaly; Pregnancy Complications, Infectious; Bruxism; Deglutition Disorders; Zika Virus; Brazil
PubMed: 37578656
DOI: 10.1007/s00784-023-05137-5 -
American Journal of Medical Genetics.... Sep 2023Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia,...
Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.
Topics: Male; Humans; DNA-Binding Proteins; Muscle Hypotonia; Transcription Factors; Face; Abnormalities, Multiple; Micrognathism; Intellectual Disability; Hand Deformities, Congenital; Neck
PubMed: 37654076
DOI: 10.1002/ajmg.c.32056 -
Nature Communications Feb 2024Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we...
Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.
Topics: Humans; Spine; Musculoskeletal Abnormalities; Alleles; Exome; T-Box Domain Proteins
PubMed: 38321032
DOI: 10.1038/s41467-024-45442-5