Özet:
Background—Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with
classic features, including short stature, microcephaly, developmental delay, neuropathy, and
photosensitivity. New genomic approaches offer improved molecular diagnostic potential.
Methods—Whole-exome sequencing was employed to study a consanguineous extended family
with severe short stature and variable presentations of peripheral neuropathy, lipoatrophy,
photosensitivity, webbed neck, and hirsutism.
Results—We identified a novel homozygous ERCC6 variant at the donor splice site of intron 9
(c.1992+3A>G), which was predicted to only slightly perturb splicing efficiencies. Assessment of
primary fibroblast-derived mRNAs, however, revealed a dominant splicing species that utilized an
unsuspected putative donor splice site within exon 9, resulting in predicted early protein
termination (p.Arg637Serfs*34).
Conclusions—We describe a new splicing ERCC6 defect causal of Cockayne syndrome. The
application of exome sequence analysis was integral to diagnosis, given the complexity of
phenotypic presentation in affected family members. The novel splicing defect, furthermore,
illustrates how a seemingly minor change in the relative strength of a splice site can have
significant biological consequences.