MCPH1: A Novel Case Report and a Review of the Literature

Abstract

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, MCPH1 or Microcephalin, encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on MCPH1 function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1-8 of MCPH1. We compare the patients' characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution.

Keywords: MCPH1; MRI; SNP array; microcephaly; simplified gyral pattern.

Figure 1

Brain MRI (turbo spin echo T2) performed at 3 days of life. (a) Sagittal view: microencephaly with flat frontal bone and enlarged posterior fossa with large cisterna magna. (b) Axial view: posteriorly enlarged lateral ventricles and fronto-polar lissencephaly with increased cortical thickness.

Figure 2

Brain MRI follow-up at 2 years 1 month of age. (a) Spin echo T1, sagittal view: enlarged posterior fossa with large cisterna magna. (b) Inversion recovery, coronal view: posteriorly enlarged lateral ventricles. (c) Fluid-attenuated inversion recovery, axial view: enlarged ventricles and fronto-polar simplified gyral pattern. (d) Turbo spin echo T2, axial view: right periventricular nodular heterotopia (arrow).

Figure 2

Brain MRI follow-up at 2 years 1 month of age. (a) Spin echo T1, sagittal view: enlarged posterior fossa with large cisterna magna. (b) Inversion recovery, coronal view: posteriorly enlarged lateral ventricles. (c) Fluid-attenuated inversion recovery, axial view: enlarged ventricles and fronto-polar simplified gyral pattern. (d) Turbo spin echo T2, axial view: right periventricular nodular heterotopia (arrow).

Figure 3

Facial features of our patient at 4 years 7 months of age: (a) front, (b) profile.

Figure 4

Schematic representation of the two main MCPH1 transcripts and of the full-length protein, on which variants reported in Table S1 have been mapped. ex: exon; gray boxes: UTRs; black boxes: exons; *: stop codon; del: deletion; dup: duplication; BRCT: BRCA1 C-terminal domain; Cb: condensin II binding region; text in red: frameshift/nonsense variants; text in blue: compound heterozygous variants; text in green: deletion identified in our patient.