Research for Genetic Factors Involved in Congenital Dislocation of Hip: Genome-wide Association Study in Grand West France
Condition: Congenital Hip Dislocation
MeSH terms: Joint Dislocations; Hip Dislocation; Hip Dislocation, Congenital; Developmental Dysplasia of the Hip
Study type: Observational

Summary: 
      The main objective is to identify the genes involved in congenital dislocation of the hip.

      The secondary objectives are to measure the association between mechanical risk factors and
      congenital dislocation of hip and study the interactions between these factors and genetic
      factors.
    

Detailed description: 
      Congenital hip dislocation (CHD) is one of the most frequent skeleton abnormalities in the
      Caucasian population (incidence: 2-10 / 1000). This disease results from an abnormality of
      the reports of the femoral head with the acetabulum, generated by a morphological defect of
      the cavity and / or joint hypermobility.

      This condition is now defined as a multifactorial disease involving in the one hand,
      mechanical factors related to the conditions of pregnancy and childbirth, and secondly,
      genetic factors suggested by ethnic predisposition and familial aggregation observed. Despite
      the neonatal screening, CHD remains a public health problem because of its high frequency,
      because of the functional handicap which it leads in case of late diagnosis and of its
      natural evolution to coxarthrosis.

      CHD was the object of a significant number of publications on the difficult aspects of its
      screening and treatment but, at the moment, few data are available on the genetic factors
      involved.

      The genetic studies led on the CHD based on studies of case-control associations, focused on
      candidate genes, and genetic linkage analysis, two strategies classically used in genetic
      epidemiology.

      To date, these strategies did not allow to elucidate the genetic determinism of the
      pathology.

      The considerable progress made in recent years both in the field of knowledge of the human
      genome and its variability, in the development of methodological and technological tools
      allow to better understand the genetic determinism of complex diseases such as CHD.

      The development of the techniques of broadband sequencing, new generation said sequencing
      (NGS for Next Generation Sequencing) makes indeed accessible the sequencing of the whole
      genome or of the set of its coding regions (exome) and now allows identify rare variants,
      that is to say variants having a minor allele frequency of less than 1%. These variants were
      previously not recognizable by the strategies traditionally used in genetic epidemiology,
      which are based on the study of common variants (minor allele frequency of ≥ 5%) listed in
      the public databases of the human genome .

      The NGS sequencing technique makes it possible to address the problem of the study of complex
      diseases in a new light and it appears necessary to apply this strategy to the CHD to search
      for genetic factors involved in the pathology.

      The genetic analysis strategy initially envisaged consisted of a genome wide association
      study (GWAS), which aims to genotype millions of frequent genetic markers scattered along the
      genome and to test their association with the disease.

      The technological advances made in the field of molecular genetics since the implementation
      of the GENETHIP protocol have made it possible to envisage new strategies to identify the
      genetic factors involved in a complex disease such as CHD. These strategies include
      high-throughput sequencing - Next Generation Sequencing (NGS) - which now makes sequencing of
      all coding regions of the genome (exome) possible. Beyond the frequent variants, this
      technique also makes it possible to identify rare variants (frequency of the minor allele
      <1%), not analyzed by the strategy initially envisaged in this project.

      It was therefore decided to adopt this new strategy in the GENETHIP study. The sample size
      could be reduced as the average frequency of the minor allele is lower with this type of
      study.

      The new genetic strategy adopted nevertheless requires the inclusion of selected phenotypes,
      which leads to recruiting exclusively patients with a family history of congenital hip
      disorders and excluding those who have had a presentation by the seat (main mechanical risk
      factor of the CHD). This is intended to better target the genetic character of the pathology.
    

Intervention name(s): Sampling saliva
Intervention type(s): Other
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Case group