A novel homozygous KY variant causing a complex neurological disorder

Highlights

• Patients with a homozygous KY frameshift variant are presented.

• We report mixed upper and lower motor neuron features in the same individual.

• Additional features include toe walking, pes equinovarus, and a speech disorder.

• KY-associated disorders manifest in a broad phenotype spectrum.

Abstract

Mutations in the gene kyphoscoliosis peptidase (KY) are known to cause myofibrillar myopathy-7 and hereditary spastic paraplegia. We investigated the genetic cause of a complex neurological phenotype in a consanguineous Pakistani family with four affected members, manifesting lower limb spasticity and weakness, toe walking, pes equinovarus, and a speech disorder. Genome-wide linkage analysis with microsatellite markers delineated chromosome 3q22.2-q24 harboring the disease gene. Whole exome sequencing was performed for two subjects, identifying a homozygous 14-bp frameshift deletion NM_178554.6:c.842_855del; p(Val281GlyfsTer18) in KY. The variant segregated with the phenotype and was absent from public databases and 100 ethnically matched controls. We confirm a novel homozygous KY variant causing a complex neurological phenotype in this family. A review of previously reported KY variants suggests that variants in this gene can cause a spectrum of neurological phenotypes.

Introduction

Homozygous loss of function variants in the gene kyphoscoliosis peptidase (KY) have primarily been implicated as a cause of rare neuromuscular phenotypes such as myofibrillar myopathy (MFM). The MFMs are a heterogeneous group of hereditary muscle diseases characterized by ectopic protein aggregates and a distinct pattern of myofibrillar disorganization (Fichna et al., 2018). Two reported variants, NM_178554.6:c.405C > A; p.(Tyr135Ter) and NM_178554.6:c.1071delG; p.(Thr358LeufsTer3) cause MFM7, characterized by pes cavus, muscular weakness and reduced reflexes in two Arab-Israeli brothers (Straussberg et al., 2016), and a Turkish girl (Hedberg-Oldfors et al., 2016), respectively. Another study reported a frameshift variant, NM_178554.6:c.51_52insTATCGACATGTGCTGTATCTATCGACAT; p.(Val18TyrfsTer56) causing hereditary spastic paraplegia (HSP) in twelve Arab-Bedouin individuals (Yogev et al., 2017). More recently, an Iranian patient with lower limb deformity and motor disorders was found to have a nonsense NM_178554.6:c.415C > T; p.(Arg139Ter) variant in KY (Ebrahimzadeh-Vesal et al., 2018).

The autosomal recessive ky mouse mutant exhibits a neuromuscular and skeletal phenotype with primary degenerative myopathy preceding chronic thoraco-lumbar kyphoscoliosis (Blanco et al., 2001). KY expression has been detected in several tissues including the brain (Fagerberg et al., 2014), and it encodes a protease which interacts with several muscle proteins such as filamin C (FLNC) and myosin-binding protein C (MYBPC1), suggesting that KY is an central part of the protein networks underlying the molecular mechanism of many limb-girdle muscular dystrophies (Beatham et al., 2004).