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 gamma-1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N-methyl-D-aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early-onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray-based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data
Key Clinical MessageWe describe the prenatal and postnatal course of an infant with a large 19p deletion. Cases such as ours will improve the knowledge of specific gene functions for every medical specialist. The goal is to allow for a more rapid diagnosis, accurate prognosis and to decrease the likelihood of complications.
Hall that loose use of the term Amyoplasia could lead to confusion. Indeed, other than capitalizing this term in the title, an AJHG-style standard at the time, we used the term amyoplasia with a lowercase ''a,'' rather than use the term Amyoplasia, throughout our manuscript to describe the state of having partial or complete absence of skeletal muscles in a body segment. 1,2 Moreover, we agree that Amyoplasia is, in most cases, unlikely to be due to germline mutations. But we do think it reasonable to hypothesize that somatic mosaicism for large-effect alleles underlies the condition in some persons with Amyoplasia. Such an observation would be consistent with the lack of familial cases. As we also noted, reports of ''familial amyoplasia'' accompanied by identification of the underlying pathogenic variant do exist. [3][4][5] But the ''amyoplasia'' in such reports is typically limited to the upper or lower limbs, 6 which is again why we stated that ''at least in some families with amyoplasia [lower case], large-effect risk alleles appear to be segregating.'' Addressing a couple of additional points more precisely will further clarify the issue for readers. First, we don't know how many affected persons we reported had complete absence of the skeletal muscles of the ankle and foot. The one individual we described with this finding was the only person who underwent sophisticated imaging and pathological exam of the affected limb. Although we don't think the complete absence of skeletal muscles in a limb segment is likely to be a common finding, it was striking enough to draw attention to it, particularly because the zebrafish model we reported points toward a potential mechanism for muscle loss in persons with pathogenic MYLPF variants. Moreover, although one or several muscles have been reportedly absent in individuals with various arthrogryposis conditions, we are not aware of other reports of absence of all of the muscles of a limb segment. If such persons exist, we would be delighted to study them. Finally, we would like to emphasize that this work was a collaborative effort among multiple groups: the Bamshad group contributed the human clinical genetic analyses, and the Amacher group contributed the zebrafish model and analysis.
Mutations in MYLPF cause a novel segmental amyoplasia that manifests as distal1 arthrogryposis 2 3 Abstract 72 We identified ten persons in six consanguineous families with Distal Arthrogryposis (DA) who 73 had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each 74 affected person was homozygous for one of two different rare variants (c.470G>T, 75 p.(Cys157Phe) or c.469T>C, p.(Cys157Arg)) affecting the same residue of myosin light chain, 76 phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A, 77 p.(Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an 78 eighth family comprised of seven individuals with dominantly-inherited DA, a c.98C>T, 79 p.(Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both 80 dominant and recessively inherited DA. Mylpf protein models suggest that the residues 81 associated with dominant DA interact with myosin whereas the residues altered in families with 82 recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot 83 amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental 84 amyoplasia). To investigate the mechanism for this finding, we generated an animal model for 85 partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced 86 trunk contractile force and complete pectoral fin paralysis, demonstrating that mylpf impairment 87 most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced 88 in an appendicular muscle and was explained by reduced myosin activity and fiber 89 degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can 90 lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal 91 limb. 92 93 94 KEYWORDS 95 exome sequencing, Mendelian disease, congenital contractures, distal arthrogryposis, 96 amyoplasia, development, skeletal muscle, zebrafish 97 100 DAs are characterized by non-progressive congenital contractures of the limbs, most commonly 101 affecting the hands, wrists, feet, and ankles. Congenital contractures of the face, ocular 102 muscles, neck webbing, pterygia, short stature, and scoliosis are less frequent, variable findings 103 that facilitate delineation among the most common DA conditions: DA1 2 (MIM 108120), DA2A 3 104 (Freeman-Sheldon syndrome [MIM 193700]) and DA2B 4 (Sheldon-Hall syndrome [601680]). 105 Variants in any one of sixteen different genes can underlie DA but the overwhelming majority of 106 known pathogenic variants occur in just five genes (TPM2 (MIM 190990), TNNI2 (MIM 191043), 107 TNNT3 (MIM 600692), MYH3 (MIM 160720), MYH8 (MIM 160741)). 5,6 Yet, collectively 108 pathogenic variants are identified in only ~60% of families diagnosed with a DA, so the precise 109 genetic etiology remains unknown in nearly half of DA families. 110 Most of the genes that underlie DA encode sarcomeric components of ...
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