We are now offering testing for 7 genes associated with autosomal recessive microcephaly.  Autosomal recessive primary microcephaly (MCPH) is characterized by:

  • congenital microcephaly (3 SD below the mean at birth or at least 4 SD below the mean at later ages)
  • mental retardation, but no other neurological findings (febrile or other mild seizures do not exclude the diagnosis)
  • normal or mildly short stature that is less severe than the markedly small head circumference
  • normal weight and appearance except for the microcephaly

Mental retardation is usually mild to moderate with no progressive decline or motor deficit.  Mutations in the ASPM gene are the most common cause of MCPH.  Approximately 40% of patients (both consanguineous and non-consanguineous) with a strict diagnosis of MCPH have mutations in ASPM.  However, very few patients (<10%) with a less restrictive phenotype have mutations in ASPM.  Thus, we expect a high detection rate for high-functioning MCPH, but a lower detection rate for low-functioning MCPH, especially if associated with other anomalies.   

Several other genes, including CDK5RAP2, CENPJ, MCPH1, and STIL, have been reported to cause MCPH in a small number of families. 

Autosomal recessive microcephaly, infantile-onset seizures, and developmental delay (MCSZ) is a relatively more severe disorder.  Mental retardation is usually severe to profound with variable behavioral problems and seizures are severe and intractable.  Mutations in the PNKP gene have been described in seven families with MCSZ. 

Microcephaly, cortical malformations, and mental retardation is another more severe disorder.  Mental retardation is usually moderate to severe and brain malformations include: callosal abnormalitiesm polymicrogyria, schizencephaly and subcortical heterotopia. Some patients have also been described with seizures.  Homozygous missense and frameshift mutations in WDR62 have been reported in individuals with primary microcephaly and these various brain malformations.

Please see our information sheet for a recommended clinical work-up for microcephaly and additional information about this testing. 

We are excited to bring these and other new tests to your patients and families. Let us know if there are other tests that you would like to see offered. Please refer to our website dnatesting.uchicago.edu or contact us for more information.