Dataset Information

A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

ABSTRACT: Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC.

SUBMITTER: Latypova X

PROVIDER: S-EPMC8305424 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

Latypova Xenia X Creadore Stefan Giovanni SG Dahan-Oliel Noémi N Gustafson Anxhela Gjyshi AG Wei-Hung Hwang Steven S Bedard Tanya T Shazand Kamran K van Bosse Harold J P HJP Giampietro Philip F PF Dieterich Klaus K

Genes 20210708 7

Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs) ...[more]

PMID: 34356068

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Project description:The primary objective of this study was to evaluate the prevalence of low femoral and lumbar spine bone mineral density (BMD) in adults with arthrogryposis multiplex congenita (AMC). We performed a retrospective cohort analysis of adults with AMC who were enrolled in the French Reference Center for AMC and in the Pediatric and Adult Registry for Arthrogryposis (PARART, NCT05673265). Patients who had undergone dual-energy X-ray absorptiometry (DXA) and/or vitamin D testing were included in the analysis. Fifty-one patients (mean age, 32.9 ± 12.6 years) were included; 46 had undergone DXA. Thirty-two (32/51, 62.7%) patients had Amyoplasia, and 19 (19/51, 37.3%) had other types of AMC (18 distal arthrogryposis, 1 Larsen). Six patients (6/42, 14.3%) had a lumbar BMD Z score less than - 2. The mean lumbar spine Z score (- 0.03 ± 1.6) was not significantly lower than the expected BMD Z score in the general population. Nine (9/40, 22.5%) and 10 (10/40, 25.0%) patients had femoral neck and total hip BMD Z scores less than - 2, respectively. The mean femoral neck (- 1.1 ± 1.1) and total hip (- 1.2 ± 1.2) BMD Z scores in patients with AMC were significantly lower than expected in the general population (p < 0.001). Femoral neck BMD correlated with height (rs = 0.39, p = 0.01), age (rs = - 0.315, p = 0.48); total hip BMD correlated with height (rs = 0.331, p = 0.04) and calcium levels (rs = 0.41, p = 0.04). Twenty-five patients (25/51, 49.0%) reported 39 fractures. Thirty-one (31/36, 86.1%) patients had 25-hydroxyvitamin D levels less than 75 nmol/l, and 6 (6/36, 16.7%) had 25-hydroxyvitamin D levels less than 75 nmol/l. Adults with AMC had lower hip BMD than expected for their age, and they more frequently showed vitamin D insufficiency. Screening for low BMD by DXA and adding vitamin D supplementation when vitamin D status is insufficient should be considered in adults with AMC, especially if there is a history of falls or fractures.

Project description:BackgroundBovine arthrogryposis multiplex congenita (AMC) is a syndromic term for a congenital condition characterized by multiple joint contractures. Rare inherited forms of bovine AMC have been reported in different breeds. For AMC in Angus cattle a causative genomic deletion encompassing the agrin (AGRN) gene, encoding an essential neural regulator that induces the aggregation of acetylcholine receptors (AChRs), is known. In 2015, three genetically related cases of generalized AMC affecting Red dairy calves were diagnosed in Denmark.ResultsThe family history of three affected calves suggested an autosomal recessive inheritance. Single nucleotide polymorphism (SNP) genotyping showed a single genomic region of extended homozygosity of 21.5 Mb on chromosome 19. Linkage analysis revealed a maximal parametric LOD score of 1.8 at this region. By whole genome re-sequencing of the three cases, two private homozygous non-synonymous variants were detected in the critical interval. Both variants, located in the myosin phosphatase Rho interacting protein (MPRIP) and the cholinergic receptor nicotinic beta 1 subunit gene (CHRNB1), were perfectly associated with the AMC phenotype. Previously described CHRNB1 variants in humans lead to a congenital myasthenic syndrome with impaired neuromuscular transmission. The cattle variant represents a single base deletion in the first exon of CHRNB1 (c.55delG) introducing a premature stop codon (p.Ala19Profs47*) in the second exon, truncating 96 % of the protein.ConclusionsThis study provides the first phenotypically and genetically characterized example of a bovine AMC phenotype that represents an inherited neuromuscular disorder corresponding to human congenital myasthenic syndrome. The identified CHRNB1 loss of function variant is predicted to have a deleterious effect on fetal AChR function, which could explain the lethal phenotype reported in this study. The identification of this candidate causative mutation thus widens the known phenotypic spectrum of CHRNB1 mutations and enables selection against this pathogenic variant in Red dairy cattle.

Project description:BackgroundThe rarity of pregnancies in women with arthrogryposis multiplex congenita (AMC) could lead to healthcare providers having limited exposure to these cases. Consequently, they may be less familiar with the possibilities and challenges associated with pregnancies in women affected by AMC. AMC is an umbrella term for a disorder with multiple contractures at birth, having a broad spectrum of causes, onset and severity of expression. A clinical classification describing the phenotype is Group 1 with primary limb involvement, Group 2 with musculoskeletal involvement plus other system anomalies, and Group 3 with musculoskeletal involvement plus central nervous system dysfunction and/or intellectual disability. A scoping review was conducted to review available literature on documented cases of pregnancies in women with AMC, with the following aims: (1) to outline the maternal, fetal and neonatal outcomes; (2) to describe AMC stability during and after pregnancy (worsening of symptoms due to contractures, increased muscle weakness, pain or lung involvement); and (3) to summarize counselling aspects during pregnancy for expecting mothers who have AMC.ResultsThis scoping review included 27 manuscripts reporting on 43 women with 82 pregnancies, of whom 18 in Group 1, 20 in Group 2, 2 in Group 3, and 3 with an unknown type. Details on pregnancy-related outcomes could be depicted from 26 of the 43 women concerning 31 pregnancies. Among these pregnancies, 74% (23/31) had a cesarean section delivery, of which 74% (17/23) were elective. Children were born preterm before week 37 in 7 of 31 pregnancies (22%). A birth weight below the 10th percentile was seen in 6 of the 24 (25%) with a reported birth weight. The course of the pregnancy was uneventful in 16 of the 26 women (62%). Pregnancy had a limited negative influence on AMC stability except for three cases with a transient worsening of lung function.ConclusionsGathering the information of the case histories revealed that the majority of the reported women had Distal Arthrogryposis with stable AMC during pregnancy and after delivery. The risk to have a cesarean section, preterm labour or a small for gestational age child is higher in this group than in the general population. Insights obtained by this review emphasized to offer (pre)pregnancy counselling and care by a multidisciplinary team tailored to the women's type of AMC, to ensure optimal preparation for both obstetric, genetic, neurologic, pulmonary and anesthetic care during pregnancy, delivery and postpartum period.

Dataset Information

A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

Publications

A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

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