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The molecular landscape of ASPM mutations in primary microcephaly
  1. Adeline Nicholas (akn24{at}cam.ac.uk)
  1. CIMR Cambridge, United Kingdom
    1. Geoff Woods (cw347{at}cam.ac.uk)
    1. University of Cambridge, United Kingdom
      1. Eric Swanson (wbd{at}genetics.bsd.uchicago.edu)
      1. University of Chicago, Department of Human Genetics, United States
        1. James Cox (jjc39{at}cam.ac.uk)
        1. University of Cambridge, United Kingdom
          1. Gulshan Karbani (gakarbani{at}yahoo.co.uk)
          1. Department of Clinical Genetics, St James’s University Hospital, Beckett Street, Leeds, United Kingdom
            1. Saghira Malik (saghira.malik{at}leedsth.nhs.uk)
            1. Department of Clinical Genetics, St James’s University Hospital, Beckett Street, Leeds, United Kingdom
              1. Kelly Springel (k.springell{at}leeds.ac.uk)
              1. LIMM University of Leeds, United Kingdom
                1. Daniel Hampshire (d.hampshire{at}sheffield.ac.uk)
                1. University of Sheffield, United Kingdom
                  1. Mustaq Ahmed (mustaq.ahmed{at}leedsth.nhs.uk)
                  1. Department of Clinical Genetics, St James’s University Hospital, Beckett Street, Leeds, United Kingdom
                    1. Jacquelyn Bond (j.bond{at}leeds.ac.uk)
                    1. LIMM University of Leeds, United Kingdom
                      1. Daniela Di Benedetto (ddibenedetto{at}oasi.en.it)
                      1. Laboratory of Genetic Diagnosis, I.R.C.C.S, Troina, Italy
                        1. Marco Fichera (mfichera{at}oasi.en.it)
                        1. Genetic Diagnosis, I.R.C.C.S, Troina, Italy
                          1. Corrado Romano (cromano{at}oasi.en.it)
                          1. Unit of Paediatrics and Medical Genetics, I.R.C.C.S, Troina, Italy
                            1. William Dobyns (wbd{at}genetics.bsd.uchicago.edu)
                            1. Department of Genetics, University of Chicago, United States

                              Abstract

                              Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during foetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, eleven (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3(7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH-associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. This study confirms that mutations in ASPM are the commonest cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype and that ASPM testing in primary microcephaly is clinically useful.

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