Autosomal recessive primary microcephaly (MCPH) is characterized by congenital microcephaly and mental retardation (MR) with no other neurological findings.  Mutations in the ASPM gene are the most common etiology of MCPH, causing approximately 40% of cases with a strict diagnosis of MCPH.  Several other genes, including CDK5RAP2, CENPJ, MCPH1, STIL, and CEP152 have been reported to cause MCPH in a small number of families.  These genes are all thought to play a role in cell division.  

Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile include a receding forehead, large eyes, beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and mental retardation.  Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD) are both characterized by intrauterine growth retardation, dwarfism, and microcephaly.   MOPD is differentiated from Seckel syndrome by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Mutations in the PCNT gene have been described in many patients with MOPD or Seckel syndrome.  The PCNT gene is also thought to play a role in cell division.

Recently, Al Dosari, et al (2010) reported a homozygous splice site mutation, IVS11-1G>C, in the CENPJ gene in several members of a consanguineous family from Saudi Arabia with Seckel syndrome.  Mutations in CEP152 have also been identified in Turkish, Italian and South African families with Seckel syndrome.  Thus, it seems that MCPH, Seckel syndrome, and MOPD may all be part of a spectrum of disorders with a similar etiology.

We report molecular testing on a six year-old female with severe growth deficiency, microcephaly, developmental delay, and facial features resembling Seckel syndrome.  MRI of her brain is similar to that seen in patients with MCPH.  Full gene sequencing of CENPJ revealed a homozygous novel sequence change, IVS11-15A>G. In silico analysis using splice site prediction programs predicts that this sequence change creates a possible new splice acceptor site at the site of mutation.  Functional studies of this sequence change are pending. In addition, DNA from a subsequent affected pregnancy was also homozygous for this sequence change. It is interesting that our patient with a Seckel-like phenotype also had a possible splicing mutation in exon 11 of the CENPJ gene similar to the Seckel syndrome patients described by Al Dosari et al (2010) also with a splicing mutation affecting exon 11 of the CENPJ gene. It is possible that mutations affecting the splicing of this region of the CENPJ gene may result in more of a Seckel/MOPD phenotype than an MCPH phenotype. This patient illustrates the evolving clinical spectrum including MCPH, Seckel syndrome and MOPD.

This poster (#446) will be presented at the ACMG Annual Meeting by Melissa Dempsey,  our genetic counselor, Friday March 30: 10:30-11:30 am. Stop by and learn more.