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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Medical Genetics 1/2017

Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip

BMC Medical Genetics > Ausgabe 1/2017
Sulman Basit, Alia M. Albalawi, Essa Alharby, Khalid I. Khoshhal
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Electronic supplementary material

The online version of this article (doi:10.​1186/​s12881-017-0393-8) contains supplementary material, which is available to authorized users.



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.


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.


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.


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.
Additional file 1: Figure S1. Flow chart showing steps performed during generation of annotated variant file from raw data. (JPG 83 kb)
Additional file 2: Figure S2. Variant filtration process illustrating the exome filtering scheme in two affected individuals. Panel 1: Genes containing rare variants (1% in 1000G/ExAC/in-house database; absent from dbSNP) and in accordance with an autosomal dominant inheritance with incomplete penetrance (shared between affected samples III:5 and IV:2). ACOT8, ADCK1, AGMO, ANGPT4, ANKS3, ATP2B4, BARHL1, C12orf44, C18orf56, CACTIN, CCM2L, CEACAM4, CRISPLD2, CTAGE7P, CTSA, CTSE, DAGLB, DAZAP2, DCTN4, DENND1B, EDEM1, EMG1, FAM154A, FAM19A2, GSK3A, HIPK1, HMCN2, HNRNPUL1, HSPG2, INCENP, INTS1, IRG1, KCNIP4, KHSRP, LEPREL2, LPPR3, MAN1C1, MICALCL, MREG, MUC5B, NAV1, NEURL2, NPR2, NUCKS1, PCSK5, PDS5A, PLCG2, POMT1, PPL, PRDM7, PRKAB1, SEZ6L, SLC6A12, SLC7A5, SLIT2, ZCCHC8, ZNF335, ZNF648, ZNF780A. (JPG 128 kb)
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