Monthly Archives: March 2014

Gene identification in rare skeletal diseases

An interesting historical breakdown of gene identification for rare skeletal diseases in the 25 years from 1988 to 2011.

GSD gene identification

What becomes apparent is that technology clearly drives the process of gene discovery and that there are ‘peaks in discovery’ that are closely aligned with ‘new’ technologies.

  • The availability of highly informative microsatelllite markers, which could even be assembled into panels for multiplexing (pioneered by Jim Weber in Marshfield Wisconsin), heralded the first increase in gene identification starting in the early to mid 1990’s.
  • This approach was massively enhanced with the publication of the Human Genome, which allowed a rapid transition from candidate region to candidate genes. For example, in our multiple epiphyseal dysplasia (MED) study of 2001 we went from a linked candidate region of 60cM to three candidate genes; TIMP3, SDC1 and MATN3 – we chose wisely  Chapman et al 01.
  • High throughput SNP analysis aided in the identification of numerous genes responsible for recessive skeletal diseases through homozygosity mapping.
  • Most recently arrays and next generation sequencing has completely revolutionised disease gene discovery in rare (skeletal) diseases.



A super example of gene discovery using exome sequencing comes from Andreas Zankl, Matt Brown and colleagues.

In summary, exome sequencing of both parents and the affected siblings in this family identified:-

  • 90% of targeted nucleotides had coverage of >four-fold
  • 79% of targeted nucleotides had coverage >ten-fold
  • ~15,000 SNPs identified following bioinformatic filtering!


  • >96% SNPs were reported in the recent dbSNP database and were therefore excluded from further analysis as unlikely to cause this rare disease.
  • Following the functional annotation of the remaining novel SNPs, focused analyses on a set of 483 unique novel coding non-synonymous SNPs that were detected in at least one sample.
  • Careful selection of ‘mode of inheritance’ allowed the identification of just four candidate genes.
  • In all but one gene the detected missense mutations were predicted to be tolerated in terms of effect upon protein function.

The single remaining candidate gene carried two novel alleles :-

  • One creating a premature stop codon.
  • One causing a missense mutation predicted to have a damaging effect on protein function.
  • POP1 a strong candidate for the disease-causing gene in this family.

Needless to say that this story made a great 2nd year undergraduate lecture Exome Lecture.

It’s here at last……

……..the start of the English first class cricket season!

M.C.C. v Durham at Abu Dhabi – I know the first game is not being played in England this year, but have you seen the weather forecast for tomorrow !

cricketOver 125 years of history and tradition

Okay, so picture on the left shows the great Australian batsman Victor Trumper, but he was a ‘great’ of the golden age of cricket (1890-1914) and the picture of him ‘jumping out to drive” taken by Bedlam at the Oval in 1902 is a classic. Another classical batsman is Ian Bell of Warwickshire and England.

But of course, the County Championship 2014………Yorkshire-County-Cricket-Club


Diagnostic exome sequencing for rare diseases

A very exciting initiative recently announced……..

download-1Global Genes Partners With SWAN USA To Help Undiagnosed Rare Disease Patients Seek A Medical Diagnosis Through Free Whole Exome Sequencing Program

The Global Genes Project, a non-profit rare disease advocacy organisation and Syndromes Without A Name USA (SWAN USA), another non-profit support organisation for patients with undiagnosed syndromes, are funding an initiative to provide 30 patients free whole exome sequencing.

Full story here.


Similar initiatives in the UK include Genomics England and Deciphering Developmental Disorders.



Is there a need for ‘next generation diagnostics’ for rare skeletal diseases?

Yes of course there is; this is a large group of clinically variable and genetically heterogeneous diseases, moreover, many of the candidate genes are very large and have numerous exons.


The Greenwood Genetic Center has recently developed and employed a “NGS Skeletal Dysplasia Panel”. The 10 genes included on the panel account for more than 30 distinct clinical phenotypes. They have previously suggested that an estimated 90% of individuals with a skeletal dysplasia have a mutation in one of these ten genes. Whilst this number is likely to be optimistic, and indeed their own study suggest 45% of patients is a more accurate figure, it non-the-less suggests a good clinical utility for next generation diagnostics for rare skeletal diseases.

See study Greenberg NGS Panel study here AMP2013_MJ-Basehore.

Other companies offering NGS diagnostics include:-

Connective Tissue Gene Tests here (USA).

Insight Medical Genetics here (USA).

Apser Reprogenetics here (Estonia).

Emory Genetics Laboratory here, which includes 163 target genes. They also offer an MED specific panel of all 7 genes (USA).

Munroe-Meyer Institute here (USA).

Disappointingly the UK has been slow to translate this new technology into the clinical diagnostic setting.

Our first publication for 2014


“Genotype to phenotype correlations in cartilage oligomeric matrix protein (COMP) associated chondrodysplasias” published in European Journal of Human Genetics.

March 5th

Available here ejhg201430a with supplemental information here ejhg201430x1.



The first mutations in COMP were identified in 1995 in patients with both PSACH and MED and subsequently there has been over 30 publications describing COMP mutations in at least 250 PSACH–MED patients.

However, despite these discoveries, a methodical analysis of the relationship between COMP mutations and phenotypes has not been undertaken. In particular, there has, to date, been little correlation between the type and location of a COMP mutation and the resulting phenotype of PSACH or MED.

To determine if genotype to phenotype correlations could be derived for COMP, we collated 300 COMP mutations, including 25 recently identified novel mutations. The results of this analysis demonstrate that mutations in specific residues and/or regions of the type III repeats of COMP are significantly associated with either PSACH or MED.

This newly derived genotype to phenotype correlation may aid in determining the prognosis of PSACH and MED, including the prediction of disease severity, and in the long term guide genetic counselling and contribute to the clinical management of patients with these diseases.