A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene

Abstract

We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T4A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations. INTRODUCTIONSkeletal dysplasias with multiple joint dislocations is a heterogeneous group of disorders comprising~10 distinct entities. 1 Spondyloepimetaphyseal dysplasia (SEMD) with joint laxity type 2 (leptodactylic type, Hall type or SEMD-JL2; MIM 603546) is an autosomal dominant skeletal dysplasia with short stature, multiple joint dislocations and/or laxity, delayed ossification of carpals, small carpus, severe epiphyseal and mild metaphyseal changes, mild vertebral body deformities and gracile metacarpals. 2 Missense variants affecting one of two amino acids in the motor domain of the kinesin family member KIF22 have been identified to cause SEMD-JL2. 3,4 Key features of SEMD with joint laxity, type 1, with or without fractures (SEMD-JL1; MIM 271640), which is caused by biallelic variants in B3GALT6, 5,6 are joint laxity and dislocations and SEMD. Affected individuals show facial dysmorphism, kyphoscoliosis at birth, talipes equinovarus, cleft palate and congenital heart disease. 7 Another SEMD-JL2-like phenotype is associated with a homozygous missense variant in NIN. 8 Here, we report two brothers with a new type of autosomal recessive SEMD with laxity and joint dislocations. We used single-nucleotide polymorphism (SNP) array analysis and whole-exome sequencing (WES) to identify a homozygous nonsense variant in EXOC6B in the affected siblings.

Untapped opportunities for rare disease gene discovery in India

“…For example, in a cohort of 508 Indian skeletal dysplasia families, 82% had a recessive condition (Uttarilli et al, 2019). This is also illustrated well by discovery of extremely rare diseases that are precipitated by consanguinity that is evident or distant (Girisha, Kortum, et al, 2016; Girisha et al, 2019).…”

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

“…Both probands and one healthy sibling were subjected to WES as described previously. 4,5 We initially hypothesized a Mendelian recessive trait. By employing our internal pipeline to prioritize potentially disease-causing mutations, 4,5 we did not identify any rare, potentially pathogenic biallelic variants in the affected siblings (data not shown).…”

“…4,5 We initially hypothesized a Mendelian recessive trait. By employing our internal pipeline to prioritize potentially disease-causing mutations, 4,5 we did not identify any rare, potentially pathogenic biallelic variants in the affected siblings (data not shown). WES data were then analyzed for heterozygous variants (non-synonymous, frameshift, and intronic variants at exon-intron boundaries ranging from −10 to +10) absent in dbSNP138, the 1000 Genomes Browser, the NHLBI Exome Sequencing Project Exome Variant Server (EVS), and the Exome Aggregation Consortium (ExAC) Browser, 6 shared by both affected subjects, and absent in the healthy sibling.…”

A review of skeletal dysplasia research in India

“…The reports on association of CSPP1 mutations in Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy, recurrent BGN mutations in X-linked spondylo-epi-metaphyseal dysplasia (XLR-SEMD), IFT52 variant in a human skeletal ciliopathy, and homozygous nonsense EXOC6B variant in an uncharacterized autosomal recessive SEMD with joint laxity and dislocations were some important Indian contributions. [ 57 58 59 60 ] Though EXOC6B is yet to be confirmed as a cause of SD by functional studies and further reports, IFT52 is now validated by functional studies and second index case. [ 61 ] Few other reports on novel gene discovery are also noteworthy.…”

“…These strategies have resulted in discovery of ACP5 , CSPP1 , BGN , IFT52 , EXOC6 , sFRP4 , IFT57 , and EXTL3 genes. [ 55 56 57 58 59 60 61 62 63 64 ]…”