Abstract:
Background: Hypodontia is the most common developmental anomaly in humans. It occurs
as a consequence to disruption of genes involved in the signaling pathways of tooth
development. Mutations in candidate genes such as Msx1, Pax9 and Axin2 have been
associated with isolated tooth agenesis. Syndromic hypodontia involves numerous
syndromes where hypodontia is part of the clinical spectrum of anomalies. The aim of this
study was to investigate the genetic determinants of syndromic and non-syndromic tooth
agenesis in five Palestinian families.
Methods: Five Palestinian families displaying variable forms of hypodontia were recruited
for blood sampling. A combination of homozygosity mapping, whole exome sequencing and
Sanger sequencing were used to identify the causative mutations. The identified mutations
were validated by testing 200 normal controls. Functional validation using reverse
transcriptase PCR was conducted where applicable on selected tissues.
Results: Direct sequencing identified two novel heterozygous mutations in the coding
sequence of Msx1 gene to segregate with non-syndromic autosomal dominant hypodontia in
one family. The first is a missense mutation (c.306 C>T, p.P24L). The second is a loss-offunction
splicing mutation (c.704 A>T) that has been functionally shown to produce
aberrant splicing in adult oral periosteal tissue, with a shift in the reading frame and a
premature stop codon yielding a truncated Msx1 sense transcript. Whole exome sequencing
revealed that a novel homozygous variant of Kremen1 gene (c.679 T>C, p.F209S) is
responsible for autosomal recessive syndromic oligodontia alongside findings of ectodermal
dysplasia in four families. Two hundred Palestinian controls were negative for the Msx1
mutations and gave a heterozygosity value of 1/200 for the Kremen1 variant.
Conclusion: Our results expand the genetic spectrum of syndromic and non-syndromic tooth
agenesis with the introduction of Kremen1 as a novel candidate gene for a distinct form of
ectodermal dysplasia.
Keywords: tooth agenesis, hypodontia, oligodontia, ectodermal dysplasia, Msx1, Kremen1
