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

• DOI: 10.1007/s00439-023-02528-2
• Publication Date: 2023-03-21T11:02:51Z
• Authors: Franziska Schnabel; Elisabeth Schuler; Almundher Al-Maawali; Ankur Chaurasia; Steffen Syrbe; Adila Al-Kindi; Gandham SriLakshm...; Anju Shukla; Janine Altmüller; Peter Nürnberg; Siddharth Banka; Katta M. Girisha; Yun Li; Bernd Wollnik; Gökhan Yigit
• Keywords: 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

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.