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Joint multi-ancestry and admixed GWAS reveals the complex genetics behind human cranial vault shape.Nature Communications Nov 2023The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint... (Review)
Review
The cranial vault in humans is highly variable, clinically relevant, and heritable, yet its genetic architecture remains poorly understood. Here, we conduct a joint multi-ancestry and admixed multivariate genome-wide association study on 3D cranial vault shape extracted from magnetic resonance images of 6772 children from the ABCD study cohort yielding 30 genome-wide significant loci. Follow-up analyses indicate that these loci overlap with genomic risk loci for sagittal craniosynostosis, show elevated activity cranial neural crest cells, are enriched for processes related to skeletal development, and are shared with the face and brain. We present supporting evidence of regional localization for several of the identified genes based on expression patterns in the cranial vault bones of E15.5 mice. Overall, our study provides a comprehensive overview of the genetics underlying normal-range cranial vault shape and its relevance for understanding modern human craniofacial diversity and the etiology of congenital malformations.
Topics: Child; Humans; Animals; Mice; Genome-Wide Association Study; Skull; Craniosynostoses; Facial Bones; Brain
PubMed: 37973980
DOI: 10.1038/s41467-023-43237-8 -
Journal of Medical Genetics May 2024Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies... (Review)
Review
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (, ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: ; RTS2: ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.
Topics: Rubinstein-Taybi Syndrome; Humans; CREB-Binding Protein; E1A-Associated p300 Protein; Consensus; Disease Management; Mutation
PubMed: 38471765
DOI: 10.1136/jmg-2023-109438 -
Child's Nervous System : ChNS :... Nov 2023Oxycephaly is a specific phenotype of multi-suture craniosynostosis that is often misrepresented. This study aims to review the relevant literature, clarify the... (Review)
Review
PURPOSE
Oxycephaly is a specific phenotype of multi-suture craniosynostosis that is often misrepresented. This study aims to review the relevant literature, clarify the diagnostic criteria, and present an alternate approach to its management.
METHODS
Published literature regarding oxycephaly was reviewed from 1997, when the largest series was published, until 2022. All cases at a single institution were then retrospectively reviewed.
RESULTS
Over the last 25 years, four studies met the inclusion criteria, none of which specifically defined oxycephaly. One case, in one study, was potentially consistent with the phenotype. An institutional review yielded two patients who met the original diagnostic criteria set forth by Renier and Marchac. Both patients had unexplained speech delays, mild retinal nerve fiber layer thickening, and diffuse inner table scalloping, along with the characteristic oxycephalic phenotype. One patient also had a direct intracranial pressure (ICP) measurement of 25 mmHg, and the other had a Chiari I malformation. Both were treated with posterior vault distraction osteogenesis (PVDO) to alleviate the cephalo-cranial disproportion while simultaneously allowing for turricephaly correction.
CONCLUSIONS
Oxycephaly presents with late onset multi-suture fusion. Patients have patent sutures at birth. Midface hypoplasia and known syndromic associations are absent. Patients demonstrate supraorbital recession, an obtuse fronto-nasal angle, and turricephaly without substantial brachycephaly. Over 60% of patients have symptomatic ICP elevation, the presentation of which ranges from headaches to rapidly progressive blindness. This rare form of craniosynostosis is particularly virulent and likely often missed due to diagnostic ambiguity and its relatively mild phenotype.
Topics: Infant, Newborn; Humans; Infant; Retrospective Studies; Craniosynostoses; Skull; Intracranial Pressure; Intracranial Hypertension; Osteogenesis, Distraction
PubMed: 37493719
DOI: 10.1007/s00381-023-06048-2 -
Operative Orthopadie Und Traumatologie Feb 2024Early correction of congenital scoliosis including short fusion, while minimizing both mobility restrictions and growth impairment. (Review)
Review
OBJECTIVE
Early correction of congenital scoliosis including short fusion, while minimizing both mobility restrictions and growth impairment.
INDICATIONS
Congenital scoliosis with marked deformity, proven progression, significant compensatory curves, and/or impairment of trunk balance. Furthermore, in case of compression of neural structures or pain due to secondary degeneration.
CONTRAINDICATIONS
No absolute contraindication.
SURGICAL TECHNIQUE
Posterior approach to the apex of the deformity. In the growing spine the periosteum should only be touched at the levels where fusion is planned. Insertion of pedicle screws adjacent to the hemivertebra. The posterior elements of the hemivertebra are removed: lamina, joint facets, pedicle, transverse process. Resection of the accessory proximal rib in the thoracic spine. Following blunt dissection at the lateral and anterior surface of the hemivertebra, the body of the hemivertebra and the adjacent discs are resected. The resulting gap is closed by compression via transpedicular instrumentation thus correcting the scoliotic deformity. In case of synostosis or contralateral bar formation, the concave side of the spine is dissected and the synostosis osteomized.
POSTOPERATIVE MANAGEMENT
Early mobilization on postoperative day 1. Bracing for 12 weeks depending on stability of the instrumentation. Periodic clinical and radiographic controls until the end of growth.
RESULTS
Posterior hemivertebra resection with transpedicular instrumentation is considered as the standard treatment of congenital scoliosis. Correction rates of 60-80% are achieved. Cervical and lumbosacral hemivertebrae may require an additional anterior approach. In case of synostosis, bar formation, or rib synostosis, further corrective surgeries may be necessary during growth.
Topics: Humans; Scoliosis; Treatment Outcome; Spinal Fusion; Spine; Synostosis; Retrospective Studies; Follow-Up Studies; Thoracic Vertebrae
PubMed: 37725190
DOI: 10.1007/s00064-023-00827-5 -
Journal of Obstetrics and Gynaecology... Apr 2024
Topics: Humans; Female; Klippel-Feil Syndrome; Uterus; Adult; Urogenital Abnormalities; Pregnancy
PubMed: 37984562
DOI: 10.1016/j.jogc.2023.102293 -
Human Molecular Genetics Sep 2023Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral...
Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over 20 genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families. Affected individuals presented a novel form of OFDS (OFDS-RAB34) accompanied by cardiac, cerebral, skeletal and anorectal defects. RAB34 encodes a member of the Rab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Unlike many genes required for cilium assembly, RAB34 acts selectively in cell types that use the intracellular ciliogenesis pathway, in which nascent cilia begin to form in the cytoplasm. We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function. Although some variants retain the ability to be recruited to the mother centriole, cells expressing mutant RAB34 exhibit a significant defect in cilium assembly. While many Rab proteins have been previously linked to ciliogenesis, our studies establish RAB34 as the first small GTPase involved in OFDS and reveal the distinct clinical manifestations caused by impairment of intracellular ciliogenesis.
Topics: Humans; Cilia; Orofaciodigital Syndromes; Nuclear Proteins
PubMed: 37384395
DOI: 10.1093/hmg/ddad109 -
Scientific Reports Aug 2023Craniosynostosis is characterized by the premature fusion and ossification of one or more of the sutures of the calvaria, often resulting in abnormal features of the...
Craniosynostosis is characterized by the premature fusion and ossification of one or more of the sutures of the calvaria, often resulting in abnormal features of the face and the skull. In cases in which growth of the brain supersedes available space within the skull, developmental delay or cognitive impairment can occur. A complex interplay of different cell types and multiple signaling pathways are required for correct craniofacial development. In this study, we report on two siblings with craniosynostosis and a homozygous missense pathogenic variant within the IL11RA gene (c.919 T > C; p.W307R). The patients present with craniosynostosis, exophthalmos, delayed tooth eruption, mild platybasia, and a basilar invagination. The p.W307R variant is located within the arginine-tryptophan-zipper within the D3 domain of the IL-11R, a structural element known to be important for the stability of the cytokine receptor. Expression of IL-11R-W307R in cells shows impaired maturation of the IL-11R, no transport to the cell surface and intracellular retention. Accordingly, cells stably expressing IL-11R-W307R do not respond when stimulated with IL-11, arguing for a loss-of-function mutation. In summary, the IL-11R-W307R variant, reported here for the first time to our knowledge, is most likely the causative variant underlying craniosynostosis in these patients.
Topics: Humans; Craniosynostoses; Skull; Head; Brain; Arginine
PubMed: 37596289
DOI: 10.1038/s41598-023-39466-y -
Genetics in Medicine : Official Journal... Nov 2023HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13... (Review)
Review
PURPOSE
HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance, and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations.
METHODS
Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis, and next-generation sequencing. Literature was reviewed for HOXD13 heterozygotes. Variants were annotated for phenotypic data. Severity was calculated, and cluster and decision-tree analyses were performed.
RESULTS
We identified 98 affected members of 38 families featuring 11 different (likely) causative variants and 4 variants of uncertain significance. The most frequent (25/38) were alanine repeat expansions. Phenotypes ranged from unaffected heterozygotes to severe osseous synpolydactyly, with intra- and inter-familial heterogeneity and asymmetry. A literature review provided 160 evaluable affected members of 49 families with SPD1. Computer-aided analysis only corroborated a positive correlation between alanine repeat length and phenotype severity.
CONCLUSION
Our findings support that HOXD13-protein condensation in addition to haploinsufficiency is the molecular pathomechanism of SPD1. Our data may, also, facilitate the interpretation of synpolydactyly radiographs by future automated tools.
Topics: Humans; Homeodomain Proteins; Transcription Factors; Syndactyly; Genotype; Phenotype; Pedigree; Alanine; Mutation
PubMed: 37427568
DOI: 10.1016/j.gim.2023.100928 -
Frontiers in Endocrinology 2023Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and... (Review)
Review
Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.
Topics: Female; Pregnancy; Humans; Adrenal Hyperplasia, Congenital; Antley-Bixler Syndrome Phenotype; Rupture, Spontaneous; Karyotype; Disorders of Sex Development; Cysts
PubMed: 37635957
DOI: 10.3389/fendo.2023.1226387 -
The Veterinary Clinics of North... Nov 2023There have been recent advancements in understanding the genetic contribution to pulmonary valve stenosis (PS) in brachycephalic breeds such as the French Bulldog and... (Review)
Review
There have been recent advancements in understanding the genetic contribution to pulmonary valve stenosis (PS) in brachycephalic breeds such as the French Bulldog and Bulldog. The associated genes are transcriptions factors involved in cardiac development, which is comparable to the genes that cause PS in humans. However, validation studies and functional follow up is necessary before this information can be used for screening purposes.
Topics: Animals; Dogs; Humans; Pulmonary Valve Stenosis; Craniosynostoses; Breeding; Dog Diseases
PubMed: 37423844
DOI: 10.1016/j.cvsm.2023.05.014