A mutation in F-actin polymerization factor suppresses the distal arthrogryposis type 5 PIEZO2 pathogenic variant in Caenorhabditis elegans.

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a candidate suppressor allele in the C. elegans gene gex-3. This gene is an ortholog of human NCKAP1 (NCK-associated protein 1), a subunit of the Wiskott-Aldrich syndrome protein (WASP)-verprolin homologous protein (WAVE/SCAR) complex, which regulates F-actin polymerization. Depletion of gex-3 by RNAi, or with the suppressor allele gex-3(av259[L353F]), significantly increased brood size and ovulation rate, as well as alleviating the crushed oocyte phenotype of the pezo-1(R2405P) mutant. Expression of GEX-3 in the soma is required to rescue the brood size defects in pezo-1(R2405P) animals. Actin organization and orientation were disrupted and distorted in the pezo-1 mutants. Mutation of gex-3(L353F) partially alleviated these defects. The identification of gex-3 as a suppressor of the pathogenic variant pezo-1(R2405P) suggests that the PIEZO coordinates with the cytoskeleton regulator to maintain the F-actin network and provides insight into the molecular mechanisms of DA5 and other PIEZO-associated diseases.

Homologous mutations in human ß, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation.

Mutations at a highly conserved homologous residue in three closely related muscle myosins cause three distinct diseases involving muscle defects: R671C in ß-cardiac myosin causes hypertrophic cardiomyopathy, R672C and R672H in embryonic skeletal myosin cause Freeman-Sheldon syndrome, and R674Q in perinatal skeletal myosin causes trismus-pseudocamptodactyly syndrome. It is not known whether their effects at the molecular level are similar to one another or correlate with disease phenotype and severity. To this end, we investigated the effects of the homologous mutations on key factors of molecular power production using recombinantly expressed human ß, embryonic, and perinatal myosin subfragment-1. We found large effects in the developmental myosins but minimal effects in ß myosin, and magnitude of changes correlated partially with clinical severity. The mutations in the developmental myosins dramatically decreased the step size and load-sensitive actin-detachment rate of single molecules measured by optical tweezers, in addition to decreasing overall enzymatic (ATPase) cycle rate. In contrast, the only measured effect of R671C in ß myosin was a larger step size. Our measurements of step size and bound times predicted velocities consistent with those measured in an in vitro motility assay. Finally, molecular dynamics simulations predicted that the arginine to cysteine mutation in embryonic, but not ß, myosin may reduce pre-powerstroke lever arm priming and ADP pocket opening, providing a possible structural mechanism consistent with the experimental observations. This paper presents direct comparisons of homologous mutations in several different myosin isoforms, whose divergent functional effects are a testament to myosin's highly allosteric nature.

ECEL1 related distal arthrogryposis 5D in an Indian cohort-Report of recognizable musculoskeletal phenotype and a possible founder variant.

Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.

Fast skeletal myosin-binding protein-C regulates fast skeletal muscle contraction.

Fast skeletal myosin-binding protein-C (fMyBP-C) is one of three MyBP-C paralogs and is predominantly expressed in fast skeletal muscle. Mutations in the gene that encodes fMyBP-C, MYBPC2, are associated with distal arthrogryposis, while loss of fMyBP-C protein is associated with diseased muscle. However, the functional and structural roles of fMyBP-C in skeletal muscle remain unclear. To address this gap, we generated a homozygous fMyBP-C knockout mouse (C2-/-) and characterized it both in vivo and in vitro compared to wild-type mice. Ablation of fMyBP-C was benign in terms of muscle weight, fiber type, cross-sectional area, and sarcomere ultrastructure. However, grip strength and plantar flexor muscle strength were significantly decreased in C2-/- mice. Peak isometric tetanic force and isotonic speed of contraction were significantly reduced in isolated extensor digitorum longus (EDL) from C2-/- mice. Small-angle X-ray diffraction of C2-/- EDL muscle showed significantly increased equatorial intensity ratio during contraction, indicating a greater shift of myosin heads toward actin, while MLL4 layer line intensity was decreased at rest, indicating less ordered myosin heads. Interfilament lattice spacing increased significantly in C2-/- EDL muscle. Consistent with these findings, we observed a significant reduction of steady-state isometric force during Ca2+-activation, decreased myofilament calcium sensitivity, and sinusoidal stiffness in skinned EDL muscle fibers from C2-/- mice. Finally, C2-/- muscles displayed disruption of inflammatory and regenerative pathways, along with increased muscle damage upon mechanical overload. Together, our data suggest that fMyBP-C is essential for maximal speed and force of contraction, sarcomere integrity, and calcium sensitivity in fast-twitch muscle.

Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.

We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

The range of publications on arthrogryposis multiplex congenita from 1995 to 2022-A scoping review.

Arthrogryposis multiplex congenita (AMC) is defined as "a group of congenital conditions characterized by joint contractures in two or more body areas." Given its heterogeneity, the definition of AMC has changed multiple times. This scoping review provides an overview of how AMC is defined in scientific publications, on existing knowledge and trends regarding the concept of AMC. Our review illuminates possible knowledge gaps and provides directions for future research. A scoping review was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Quantitative studies on AMC from 1995 to date were included. We summarized information about definitions/descriptions of AMC, study objectives, study designs, methods, funding, and involvement of patient organizations. A total of 2729 references were screened, and 141 articles fulfilled our inclusion criteria. Our scoping revealed that the majority of publications were cross-sectional or retrospective studies of children and young people, commonly about orthopedic management. Explicit or good definitions of AMC were provided in 86% of the cases. Recent publications on AMC mostly used consensus-based definitions. The research gaps were primarily related to adults, aging, etiology, and new medical treatment, in addition to implications on daily life.

Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder.

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis.

PURPOSE: We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. METHODS: Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. RESULTS: We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. CONCLUSION: In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome.

PIEZO2-related distal arthrogryposis type 5: Longitudinal follow-up of a three-generation family broadens phenotypic spectrum, complications, and health surveillance recommendations for this patient group.

Arthrogryposis is a heterogenous condition with a wide variety of etiological causes. It has been subdivided clinically based on the presence of additional features. Dominant gain of function (GoF) pathogenic variants in PIEZO2 have been associated with several forms of arthrogryposis. Previous reports have focused on diagnosis and clinical features. We report a three-generation family with four affected individuals with a known pathogenic GoF change p.(Glu2727del) in PIEZO2. All family members presented at birth with distal arthrogryposis and ophthalmoplegia but have varied in their subsequent clinical course with differences in mobility and joint restriction. In the longer term, other features have presented including dysphagia, back pain and spinal stenosis-like symptoms, raised intraocular pressure, and progressive restrictive lung disease. As far as we know, this is the first report detailing the longitudinal follow-up of a three-generation family which highlights potential long-term complications in patients with PIEZO2-related arthrogryposis. We present this family to demonstrate the importance of long-term follow-up for the clinical management of this group of patients.

The Hand in Distal Arthrogryposis.

Distal arthrogryposis is the second most common type of arthrogryposis after amyoplasia and is defined as arthrogryposis that affects hands and feet; it is mostly inherited in an autosomal-dominant fashion. This review discusses up-to-date background information, clinical features, and treatment of distal arthrogryposis in hands concentrating on camptodactyly, thumb-in-palm deformity, and windblown hand deformity, which are the most common and functionally limiting deformities. Treating these deformities should be individualized and follow a multidisciplinary approach. Most deformities can be initially treated nonoperatively, and if not responsive, operative treatment may be pursued to improve function. Surgery primarily aims to release soft-tissue contractures, rebalance muscle forces, and may need bony correction based on the deficits of each case. Current literature suggests that early treatment leads to better outcomes. However, reported cases are scarce, and no consensus or gold standard for treatment exists. Therefore, long-term (multicenter) studies are needed to assess outcomes and standardize the treatment of such deformities whenever possible.

Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3.

Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3, encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3. Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3, no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5' UTR splice donor site (rs557849165 in MYH3) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5' UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder.

Further delineation of MYO18B-related autosomal recessive Klippel-Feil syndrome with myopathy and facial dysmorphism.

Klippel-Feil syndrome 4 (KFS4; MIM# 616549) is an autosomal recessive disorder caused by biallelic pathogenic variants in MYO18B and comprises, in addition to Klippel-Feil anomaly (KFA), nemaline myopathy, facial dysmorphism, and short stature. We aim to outline the natural history of KFS4 and provide an updated description of its clinical, radiological, laboratory, and molecular findings. We comprehensively analyzed the medical records of 6 Saudi and 1 American patients (including 5 previously unpublished cases) with a molecularly confirmed diagnosis of KFS4. All patients had myopathy of varying severity that followed a slowly progressive or non-progressive course, affecting primarily the proximal musculature of the lower limb although hand involvement with distal arthrogryposis and abnormal interphalangeal creases was also observed. KFA and characteristic dysmorphic features, including ptosis and bulbous nose, were observed in all but two patients. The causal MYO18B variants were a founder NM_032608.5:c.6905C>A; p.(Ser2302*) variant in the Saudi patients (P1-P6) and a novel MYO18B homozygous variant (c.6660_6670del;p.[Arg2220Serfs*74]) in the American Caucasian patient (P7). We report the phenotypic and genetic findings in seven patients with KFS4. We describe the natural history of this disease, confirm myopathy as a universal feature and describe its pattern and progression, and note interesting differences between the phenotypes observed in patients with KFA and those without.

The distal arthrogryposis-linked p.R63C variant promotes the stability and nuclear accumulation of TNNT3.

BACKGROUND: Distal arthrogryposis (DA) is comprised of a group of rare developmental disorders in muscle, characterized by multiple congenital contractures of the distal limbs. Fast skeletal muscle troponin-T (TNNT3) protein is abundantly expressed in skeletal muscle and plays an important role in DA. Missense variants in TNNT3 are associated with DA, but few studies have fully clarified its pathogenic role. METHODS: Sanger sequencing was performed in three generation of a Chinese family with DA. To determine how the p.R63C variant contributed to DA, we identified a variant in TNNT3 (NM_006757.4): c.187C>T (p.R63C). And then we investigated the effects of the arginine to cysteine substitution on the distribution pattern and the half-life of TNNT3 protein. RESULTS: The protein levels of TNNT3 in affected family members were 0.8-fold higher than that without the disorder. TNNT3 protein could be degraded by the ubiquitin-proteasome complex, and the p.R63C variant did not change TNNT3 nuclear localization, but significantly prolonged its half-life from 2.5 to 7 h, to promote its accumulation in the nucleus. CONCLUSION: The p.R63C variant increased the stability of TNNT3 and promoted nuclear accumulation, which suggested its role in DA.

Mutations Q93H and E97K in TPM2 Disrupt Ca-Dependent Regulation of Actin Filaments.

Tropomyosin is a two-chain coiled coil protein, which together with the troponin complex controls interactions of actin with myosin in a Ca2+-dependent manner. In fast skeletal muscle, the contractile actin filaments are regulated by tropomyosin isoforms Tpm1.1 and Tpm2.2, which form homo- and heterodimers. Mutations in the TPM2 gene encoding isoform Tpm2.2 are linked to distal arthrogryposis and congenital myopathy-skeletal muscle diseases characterized by hyper- and hypocontractile phenotypes, respectively. In this work, in vitro functional assays were used to elucidate the molecular mechanisms of mutations Q93H and E97K in TPM2. Both mutations tended to decrease actin affinity of homo-and heterodimers in the absence and presence of troponin and Ca2+, although the effect of Q93H was stronger. Changes in susceptibility of tropomyosin to trypsin digestion suggested that the mutations diversified dynamics of tropomyosin homo- and heterodimers on the filament. The presence of Q93H in homo- and heterodimers strongly decreased activation of the actomyosin ATPase and reduced sensitivity of the thin filament to [Ca2+]. In contrast, the presence of E97K caused hyperactivation of the ATPase and increased sensitivity to [Ca2+]. In conclusion, the hypo- and hypercontractile phenotypes associated with mutations Q93H and E97K in Tpm2.2 are caused by defects in Ca2+-dependent regulation of actin-myosin interactions.

A New Intronic Variant in ECEL1 in Two Patients with Distal Arthrogryposis Type 5D.

Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c.1507-9G>A), which was predicted to affect mRNA splicing by activating a cryptic acceptor site. The frequency of the variant is very low in the general human population, and its presence in our families can be attributed to a founder effect. This study provides an updated review of the known causative mutations of the ECEL1 gene, enriching the allelic spectrum to include the noncoding sequence.

Distal arthrogryposis type 5 and PIEZO2 novel variant in a Canadian family.

The group of distal arthrogryposis (DA) disorders is characterized by congenital contractures of the distal joints. In most instances, these are genetic disorders are inherited in an autosomal dominant fashion; however, there is wide genetic and phenotypic spectrum. Distal arthrogryposis type 5 (DA5) is clinically characterized by short stature, deep-set eyes, ptosis, ophthalmoplegia, triangular facies, restrictive pulmonary function, and "firm" muscles. DA5 is produced by a gain-of-function mutations in PIEZO2 gene, encoding for an ion-channel required to convert mechanical stimulus to biological signals in mammals essential to proprioception. Heterozygous mutations in PIEZO2 may lead to other phenotypes like Gordon Syndrome and Marden Walker syndrome. In this report, we present a 3-generation family affected with DA5, who all carry a variant of unknown clinical significance c.8068A>C (p.Ser2690Arg) in the PIEZO2 gene. DA5 is a very rare condition with less than 20 cases previously reported. Our report expands the phenotype and contributes to evidence of this variant's pathogenicity.

New Insights of a Neuronal Peptidase DINE/ECEL1: Nerve Development, Nerve Regeneration and Neurogenic Pathogenesis.

Our understanding of the physiological relevance of unique Damage-induced neuronal endopeptidase (DINE) [also termed Endothelin-converting enzyme-like 1 (ECEL1)] has recently expanded. DINE/ECEL1 is a type II membrane-bound metalloprotease, belonging to a family including the neprilysin (NEP) and endothelin-converting enzyme (ECE). The family members degrade and/or process peptides such as amyloid ß and big-endothelins, which are closely associated with pathological conditions. Similar to NEP and ECE, DINE has been expected to play an important role in injured neurons as well as in developing neurons, because of its remarkable transcriptional response to neuronal insults and predominant neuronal expression from the embryonic stage. However, the physiological significance of DINE has long remained elusive. In the last decade, a series of genetically manipulated mice have driven research progress to elucidate the physiological aspects of DINE. The mice ablating Dine fail to arborize the embryonic motor axons in some subsets of muscles, including the respiratory muscles, and die immediately after birth. The abnormal phenotype of motor axons is also caused by one amino acid exchanges of DINE/ECEL1, which are responsible for distal arthrogryposis type 5 in a group of human congenital movement disorders. Furthermore, the mature Dine-deficient mice in which the lethality is rescued by genetic manipulation have shown the involvement of DINE in central nervous system regeneration. Here we describe recent research advances that DINE-mediated proteolytic processes are critical for nerve development, regeneration and pathogenesis, and discuss the future potential for DINE as a therapeutic target for axonal degeneration/disorder.

Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) 2B and mild DA in two Chinese families.

BACKGROUND: Distal arthrogryposis (DA) is a group of clinically and genetically heterogeneous disorders that involve multiple congenital limb contractures and comprise at least 10 clinical subtypes. Here, we describe our findings in two Chinese families: Family 1 with DA2B (MIM 601680) and Family 2 with mild DA. METHODS: To map the disease locus, two-point linkage analysis was performed with microsatellite markers closed to TPM2, TNNI2/TNNT3 and TNNC2. In Family 1, a positive LOD (logarithm of odds) score was only obtained at the microsatellite marker close to TPM2 and mutation screening was performed using direct sequencing of TPM2 in the proband. In Family 2, for the LOD score that did not favor linkage to any markers, whole-exome sequencing (WES) was performed on the proband. PCR-restriction fragment length polymorphism (RFLP) and bioinformatics analysis were then applied to identify the pathogenic mutations in two families. In order to correlate genotype with phenotype in DA, retrospective analyses of phenotypic features according to the TPM2 and PIEZO2 mutation spectrums were carried out. RESULTS: A heterozygous missense mutation c.308A > G (p.Q103R) in TPM2 in Family 1, and a novel variation c.8153G > A (p.R2718Q) in PIEZO2 in Family 2 were identified. Each of the two novel variants was co-segregated with the DA manifestations in the corresponding family. Bioinformatics analysis from several tools supported the pathogenicity of the mutations. Furthermore, our study suggests that there is no relation between the types or locations of TPM2 mutations and the clinical characteristics, and that different inheritance modes and mutation types concerning PIEZO2 cause distinct clinical manifestations. CONCLUSIONS: We report two novel mutations within TPM2 and PIEZO2 responsible for DA2B and mild DA in two Chinese families, respectively. Our study expands the spectrum of causal mutations in the TPM2 and PIEZO2 genes.

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology.

The Myosin Binding Protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cardiac MyBP-C is limited to the heart, and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow and fast, in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. This review characterizes MyBP-C as a whole and points out knowledge gaps that still remain with respect to skeletal MyBP-C.

Familial Gordon syndrome associated with a PIEZO2 mutation.

Gordon syndrome or distal arthrogryposis type 3 is a rare autosomal dominant disorder characterized by contractures of upper and lower limbs. It is distinguishable from other forms of distal arthrogryposis by cleft palate and short stature. Recently, Gordon syndrome has been associated to heterozygous mutations in the piezo-type mechanosensitive ion channel component 2 gene (PIEZO2). Different mutations of this gene also cause distal arthrogryposis type 5 and Marden-Walker syndrome. Dysfunction of this ion channel provides pleiotropic effects on joints, ocular muscles, and bone development. Here, we present a family with three affected individuals exhibiting multiple contractures (metacarpo-phalangeal and interphalangeal joints as well as elbow, shoulder, knee, and ankle joints), clubfeet, short stature, bifid uvula/cleft palate, and a distinct facial phenotype including ptosis. In addition, mild intellectual disability and delay in psychomotor development are obvious. The multigenerational phenotypic spectrum of Gordon syndrome is present in the 37-year-old father, his 4-year-old son and a male neonate showing typical signs of arthrogryposis in the prenatal ultrasound examination already seen at 13 week of gestation. In all affected family members, we identified the PIEZO2 mutation c.8057G>A (p.Arg2686His) by Sanger sequencing. Our analysis indicated that mild delay in psychomotor development and intellectual disability could be part of the phenotypic spectrum of Gordon syndrome. © 2016 Wiley Periodicals, Inc.