Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy

Abstract

Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

Keywords: Arab; Arthrogryposis multiplex congenita; CNTNAP1; Cerebral atrophy; Qatar.

Figure 1

Consanguineous family presenting with infantile lethal AMC. A) Pedigree of family with those known to be affected shaded in black, individuals IV:6-IV:11 are shaded grey since their presentation is similar to IV:1, IV:4 and IV:5 but was not confirmed as the same, * indicates DNA samples were available for research analysis. B) Severe joint contractures of individual IV:1. C) Axial, D) coronal and E) sagittal brain MRI images of IV:1 at 11 years of age demonstrating profound cerebral and cerebellar atrophy in comparison with an F) axial, G) coronal and H) sagittal brain MRI of a control at 5 years of age (scale bars = 2cm).

Figure 2

CNTNAP1 mutation present within family. A) Location of novel p.Leu521ProfsX12 mutation (red arrow) and known mutations (black arrows) with respect to the functional domains of the CASPR protein. B) Coronal and C) sagittal in situ hybridization for Cntnap1 on P56 mouse brain sections (Allen Brain Atlas).