A novel ECEL1 mutation expands the phenotype of distal arthrogryposis multiplex congenita type 5D to include pretibial vertical skin creases

Abstract

Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c.1163T > C, p.Leu388Pro, NM_004826) and MUSK (c.2572C > T, p.Arg858Cys, NM_005592). Both variants are predicted to have deleterious effects on the protein function, with amino acid positions highly conserved among species. The variants segregated in the family, with healthy mother, father, and sister being heterozygous carriers and the index patient being homozygous for both mutations. We report on a unique patient with a novel ECEL1 homozygous mutation, expanding the phenotypic spectrum of Distal AMC Type 5D to include vertical linear skin creases. The homozygous mutation in MUSK is of unknown clinical significance. MUSK mutations have previously shown to cause congenital myasthenic syndrome, a neuromuscular disorder with defects in the neuromuscular junction.

Expanding the Phenotypic Spectrum of ECEL1-Associated Distal Arthrogryposis

“…Distal arthrogryposis type 5 D is characterized by a wide array of clinical features including (i) musculoskeletal with foot deformities, finger contractures, and limited movement of proximal joints, recurrent hip dislocation, webbing of fingers and neck, scoliosis, kyphosis, muscle atrophy, and weakness; (ii) ophthalmological with asymmetric ptosis, strabismus, refractive errors, and ophthalmoplegia; (iii) facial with arched eyebrows, bulbous upturned nose, micrognathia, small mouth, reduced facial expression, cleft palate and tongue atrophy; (iv) others including speech difficulties, nasal voice, short stature, short neck, cryptorchidism, pterygia, faint palmar creases, and respiratory dysfunction [3][4][5][10][11][12][13][14][15][16][17][18][19]. Progressive scoliosis and weakness of limbs have been reported on long-term follow-up of these patients [11].…”

The Novel Compound Heterozygous Mutations of ECEL1 Identified in a Family with Distal Arthrogryposis Type 5D

“…There are at least 34 mutations in ECEL1 [2,6,7,18,19] (Figure 3). The structure of ECEL1 can be roughly divided into a cytoplasmic domain, a transmembrane domain, and an extracellular domain with a zinc binding motif (the 612 th -616 th AA) essential for enzymatic activity [6,7] [18,19].…”

“…Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders characterized by multiple congenital nonprogressive joint contractures, usually involving the limbs [1]. When contractures mainly involve the distal joints and affect the hands, feet, wrists, and ankles, the disease is named distal arthrogryposis (DA) [2]. DA is phenotypically and genetically heterogeneous, can be divided into at least 10 different forms (DA1-DA10), and involves more than 9 causative genes, including TPM2, TNNI2, TNNT3, MYH3, MYBPC1, MYH8, FBN2, PIEZO2, and ECEL1 [3][4][5][6].…”

Biallelic Missense Mutation in the ECEL1 Underlies Distal Arthrogryposis Type 5 (DA5D)

“…DA is caused by pathogenic mutations in the genes encoding the contractile apparatus of myofibers (2). DA overlaps clinical features with the other syndromes having both variable inter and intra-familial clinical features (1, 3, 4).…”