Homozygous loss-of-function variants in FILIP1 cause autosomal recessive arthrogryposis multiplex congenita with microcephaly

Exome sequencing Carrier Proteins/genetics Contracture Epidemiology Physiology Mechanosensitive Ion Channels in Physiology and Disease Arthrogryposis/genetics Cytoskeletal Proteins/genetics Arthrogryposis multiplex congenita Gene Microcephaly/genetics Role of Autophagy in Disease and Health Health Sciences Genetics Humans Biology Original Investigation Arthrogryposis Homozygote Pedigree 3. Good health Cytoskeletal Proteins Phenotype FOS: Biological sciences Spinal Muscular Atrophy Microcephaly Medicine Gene Therapy for Spinal Muscular Atrophy Technology Platforms Genes, Cells and Cell-Based Medicine [Topic 1] Carrier Proteins
DOI: 10.1007/s00439-023-02528-2 Publication Date: 2023-03-21T11:02:51Z
ABSTRACT
AbstractArthrogryposis multiplex congenita forms a broad group of clinically and etiologically heterogeneous disorders characterized by congenital joint contractures that involve at least two different parts of the body. Neurological and muscular disorders are commonly underlying arthrogryposis. Here, we report five affected individuals from three independent families sharing an overlapping phenotype with congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly and facial dysmorphism. Using exome sequencing, we identified homozygous truncating variants in FILIP1 in all patients. FILIP1 is a regulator of filamin homeostasis required for the initiation of cortical cell migration in the developing neocortex and essential for the differentiation process of cross-striated muscle cells during myogenesis. In summary, our data indicate that bi-allelic truncating variants in FILIP1 are causative of a novel autosomal recessive disorder and expand the spectrum of genetic factors causative of arthrogryposis multiplex congenita.
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