Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip.
BACKGROUND
Developmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle radiographic signs through mild instability to frank dislocations with acetabular dysplasia. A Saudi family with three affected individuals with DDH was identified and genetic analysis was performed to detect the possible genetic defect(s) underlying DDH in the affected members of the family.


METHODS
We performed whole genome genotyping using Illumina HumanOmni 2.5 M array and whole exome sequencing (WES) using Nextera Rapid capture kit and Illumina NextSeq500 instrument in four individuals of a family with DDH.


RESULTS
SNP data analysis did not identify any runs of homozygosity and copy number variations. Identity-by-descent (IBD) analysis on whole genome genotyping data identified a shared haplotypes on chromosome 1 in affected individuals. An analysis of the WES data identified rare heterozygous variants in HSPG2 and ATP2B4 genes in the affected individuals. Multiple prediction software predicted that the variants identified are damaging. Moreover, in silico analysis showed that HSPG2 regulates ATP2B4 expression using a variety of transcription factors.


CONCLUSIONS
Our results indicate that there might be a functional epistatic interaction between HSPG2 and ATP2B4, and DDH in the family studied is due to a combined effect of both variants. These variants are also present in the asymptomatic mother suggesting that the variants in HSPG2 and ATP2B4 are incompletely penetrant. This study provides the first evidence of digenic inheritance of DDH in a family and extends the spectrum of genetic heterogeneity in this human disorder.
Centre for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, 30001, Saudi Arabia. sbasit.phd@gmail.com.
Sulman
http://orcid.org/0000-0003-4294-6825
S
Basit
Centre for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, 30001, Saudi Arabia.
Alia M
AM
Albalawi
Centre for Genetics and Inherited Diseases, Taibah University, Almadinah Almunawwarah, 30001, Saudi Arabia.
Essa
E
Alharby
Department of Orthopedic Surgery, College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia.
Khalid I
KI
Khoshhal
D000328:Adult; D000483:Alleles; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics*; D006579:Heterozygote; D006618:Hip Dislocation, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
D019812:Heparan Sulfate Proteoglycans; C071927:perlecan; D004247:DNA; C507517:ATP2B4 protein, human; D053499:Plasma Membrane Calcium-Transporting ATPases
ATP2B4; Developmental dysplasia of the hip; Exome sequencing; HSPG2; Perlecan