-
Journal of Medical Genetics Sep 2021Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability...
BACKGROUND
Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions.
METHODS
We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required.
RESULTS
Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with and . We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations.
CONCLUSIONS
Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.
Topics: Alleles; Amino Acid Sequence; Amino Acid Substitution; Arthrogryposis; Chromosome Mapping; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; Genotype; High-Throughput Nucleotide Sequencing; Humans; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Phenotype; Sequence Analysis, DNA; Exome Sequencing
PubMed: 33060286
DOI: 10.1136/jmedgenet-2020-106901 -
Brain : a Journal of Neurology Nov 2022Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with...
Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.
Topics: Humans; Arthrogryposis; Epilepsies, Myoclonic; Epilepsy; Gain of Function Mutation; Migraine with Aura; Movement Disorders; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Spasms, Infantile; Infant, Newborn; Infant
PubMed: 35696452
DOI: 10.1093/brain/awac210 -
Journal of Medical Genetics Jun 2022Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic...
BACKGROUND
Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.
METHODS
Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.
RESULTS
We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).
CONCLUSION
New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
Topics: Arthrogryposis; Genomics; Humans; Pedigree; Phenotype; Proteins; Transcription Factors; Exome Sequencing
PubMed: 33820833
DOI: 10.1136/jmedgenet-2020-107595 -
Orthopaedics & Traumatology, Surgery &... Feb 2021Arthrogryposis multiplex congenita (AMC) consists of congenital joint contractures that affect at least two joints. There are two types: in the first, arthrogryposis is... (Review)
Review
Arthrogryposis multiplex congenita (AMC) consists of congenital joint contractures that affect at least two joints. There are two types: in the first, arthrogryposis is an additional sign in the context of various pathologies (neuromuscular diseases); in the second, it is the main and constant symptom. In the first type, the progression of the causal underlying disease must be considered. In the second type, there are two specific forms: Amyoplasia corresponds to a significant congenital absence of muscles (epigenetic disease or vascular origin) while distal arthrogryposis has a genetic component and is transmissible. The orthopedic surgeon's purpose, which is usually to enhance movement, is not appropriate for an arthrogryposis patient. One must keep in mind that without muscle, movement is impossible. The goal differs between the upper and lower limbs: for the upper limb, it is to allow grasping, and, if possible, to bring the hand to the mouth; for the lower limb, it is to ensure ambulation with plantigrade support, and the knees extended, which is the only stable position possible with little to no muscles. The rehabilitation, orthoses and/or surgical techniques are chosen to achieve this singular aim. While it may appear modest, it is crucial for patients. The goal is to achieve useful mobility, not maximum mobility. This multidisciplinary treatment, which evolves over time, must be explained to the family to get its adherence.
Topics: Arthrogryposis; Contracture; Humans; Lower Extremity; Upper Extremity; Walking
PubMed: 33321243
DOI: 10.1016/j.otsr.2020.102781 -
Science (New York, N.Y.) Jan 2023Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related...
Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.
Topics: Animals; Mice; Arthrogryposis; Contracture; Mechanotransduction, Cellular; Mutation; Sensory Receptor Cells; Ion Channels
PubMed: 36634173
DOI: 10.1126/science.add3598 -
European Journal of Paediatric Dentistry Sep 2023Otodental syndrome is a rare autosomal dominant condition characterised by a dental phenotype known as globodontia often associated with high-frequency hearing loss....
Otodental syndrome is a rare autosomal dominant condition characterised by a dental phenotype known as globodontia often associated with high-frequency hearing loss. Globodontia occurs both in the decidous and permanent dentition and affects canine and molar teeth.
Topics: Humans; Chromosome Disorders; Hearing Loss, Sensorineural; Tooth Abnormalities; Arthrogryposis
PubMed: 37668456
DOI: 10.23804/ejpd.2023.24.03.03 -
Cells Nov 2022Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic... (Review)
Review
Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.
Topics: Humans; Arthrogryposis; Lysosomes; Melanosomes; Rare Diseases; Cholestasis; Kidney Diseases
PubMed: 36429129
DOI: 10.3390/cells11223702 -
Orphanet Journal of Rare Diseases Mar 2009Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face,... (Review)
Review
Sheldon-Hall syndrome (SHS) is a rare multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs, triangular face, downslanting palpebral fissures, small mouth, and high arched palate. Epidemiological data for the prevalence of SHS are not available, but less than 100 cases have been reported in the literature. Other common clinical features of SHS include prominent nasolabial folds, high arched palate, attached earlobes, mild cervical webbing, short stature, severe camptodactyly, ulnar deviation, and vertical talus and/or talipes equinovarus. Typically, the contractures are most severe at birth and non-progressive. SHS is inherited in an autosomal dominant pattern but about half the cases are sporadic. Mutations in either MYH3, TNNI2, or TNNT3 have been found in about 50% of cases. These genes encode proteins of the contractile apparatus of fast twitch skeletal muscle fibers. The diagnosis of SHS is based on clinical criteria. Mutation analysis is useful to distinguish SHS from arthrogryposis syndromes with similar features (e.g. distal arthrogryposis 1 and Freeman-Sheldon syndrome). Prenatal diagnosis by ultrasonography is feasible at 18-24 weeks of gestation. If the family history is positive and the mutation is known in the family, prenatal molecular genetic diagnosis is possible. There is no specific therapy for SHS. However, patients benefit from early intervention with occupational and physical therapy, serial casting, and/or surgery. Life expectancy and cognitive abilities are normal.
Topics: Abnormalities, Multiple; Arthrogryposis; Child; Contracture; Cytoskeletal Proteins; Face; Female; Genetic Predisposition to Disease; Genotype; Humans; Muscle, Skeletal; Phenotype; Syndrome; Troponin T
PubMed: 19309503
DOI: 10.1186/1750-1172-4-11 -
The Turkish Journal of Pediatrics 2017Mutlu M, Aslan Y, Aktürk-Acar F, Çakır M, Erduran E, Kalyoncu M. ARC syndrome. Turk J Pediatr 2017; 59: 487-490. Arthrogryposis-renal dysfunction-cholestasis (ARC) is...
Mutlu M, Aslan Y, Aktürk-Acar F, Çakır M, Erduran E, Kalyoncu M. ARC syndrome. Turk J Pediatr 2017; 59: 487-490. Arthrogryposis-renal dysfunction-cholestasis (ARC) is an autosomal recessive multisystem disorder characterized by arthrogryposis, renal tubular dysfunction and neonatal cholestasis with low gamma glutamyl transpeptidase activity. Most of the mutations in ARC syndrome are associated with the vacuolar protein sorting 33B (VPS33B) gene on chromosome 15q26.1. Herein, we report a female newborn with ARC syndrome caused by homozygous mutations in VPS33B [IVS1-2A > C (c.97-2A > C)].
Topics: Arthrogryposis; Cholestasis; Fatal Outcome; Female; Homozygote; Humans; Infant, Newborn; Mutation; Renal Insufficiency; Vesicular Transport Proteins
PubMed: 29624233
DOI: 10.24953/turkjped.2017.04.019 -
Genes Jun 2021Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal... (Review)
Review
Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, and mice.
Topics: Animals; Arthrogryposis; Disease Models, Animal; Drosophila melanogaster; Genetic Loci; Mice; Mutation; Zebrafish
PubMed: 34203046
DOI: 10.3390/genes12060943