Abstract:
ABSTRACT
Background: Microcephaly is considered a neurodegenerative syndrome, in which the head
circumference is at least 2 SD below average which differs according to age and gender. In most
cases Microcephaly is associated with mild to severe mental retardation. Microcephaly can be
either primary (congenital) or secondary (acquired). On the other hand, Kabuki syndrome is a
rare disorder characterized by several congenital abnormalities and intellectual inability. The aim
of our study was to identify the genetic causes of both autosomal recessive Primary
Microcephaly (MCPH) and kabuki-like syndrome in three related Palestinian families.
Methods: Eleven blood samples were collected from members of the family with microcephaly,
7 blood samples from the first kabuki-like family and 5 samples from the second family with
kabuki-like syndrome, and then DNA was extracted. Whole exome sequencing then Sanger
sequencing were used to investigate the causative mutation. The mutations detected in the study
were screened by Sanger Sequencing in 100 normal controls.
Results: Whole exome sequencing revealed a novel nonsense mutation in Abnormal spindle-like
microcephaly-associated protein (ASPM) gene that results in K3228X alteration and which leads
to a premature stop codon. As for the kabuki –like syndrome, a missense homozygous mutation
(C-T) was detected in Lysine (K)-Specific Methyltransferase 2D (KMT2D) that results in
P1912L alteration. Moreover, a De novo 22q11 deletion syndrome was detected in one of
affected individual in kabuki family. The 100 controls were negative for both the ASPM and
KMT2D variants.
Conclusion: Our results revealed a novel nonsense mutation in ASPM gene that disrupts neuron
development and results in primary Microcephaly in human. A missense mutation in KMT2D
that may affect the methylation of certain genes important in development and thus leads to
IV
kabuki-like syndrome, and a De novo 22q11 deletion syndrome in a female individual in kabuki
family.
Keywords: Primary Microcephaly, kabuki syndrome, ASPM, KMT2D, methylation,
neurogenesis, 22q12DS.
