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

Author:

Schnabel FranziskaORCID,Schuler Elisabeth,Al-Maawali Almundher,Chaurasia Ankur,Syrbe Steffen,Al-Kindi Adila,Bhavani Gandham SriLakshmi,Shukla Anju,Altmüller Janine,Nürnberg Peter,Banka Siddharth,Girisha Katta M.,Li Yun,Wollnik Bernd,Yigit Gökhan

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.

Funder

India Alliance through Center for Rare Disease Diagnosis, Research and Training

National Institutes of Health

Deutsche Forschungsgemeinschaft

Deutsches Zentrum für Herz-Kreislaufforschung

Georg-August-Universität Göttingen

Publisher

Springer Science and Business Media LLC

Subject

Genetics (clinical),Genetics

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