A Novel <b><i>ERCC6</i></b> Splicing Variant Associated with a Mild Cockayne Syndrome Phenotype

Abstract

Background: Cockayne syndrome is an autosomal recessive, heterogeneous syndrome with classical 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 the 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.

Two heterozygous mutations in the ERCC6 gene associated with Cockayne syndrome in a Chinese patient

“… 18 – 20 The recent advent of next-generation sequencing has enabled the detection of ERCC6 or ERCC8 variants and aids the diagnosis of CS. 21 – 24 In the present study, the patient received a confirmed diagnosis of CS type I following clinical evaluation and identification of two compound heterozygous mutations in the ERCC6 gene using whole exome sequencing.…”

A Case of ERCC6‐Related Cockayne Syndrome Presenting with Levodopa‐Responsive Tremor Syndrome

“…This study reported the same variant in an extended Turkish family with six affected members carrying homozygous ERCC6 c.1992 + 3A > G variant with a mild-not the same described in the present study but with no life-threatening conditions-CS phenotype. 7 Severe short stature was the common finding in all six cases, and basal ganglia calcification without motor dysfunction was detected in at least two of them. 7 Since the ethnicities of the previously reported family (Turkish) 7 and the current case (Baloch) are different, it seems that they have independent founders.…”

“…7 Severe short stature was the common finding in all six cases, and basal ganglia calcification without motor dysfunction was detected in at least two of them. 7 Since the ethnicities of the previously reported family (Turkish) 7 and the current case (Baloch) are different, it seems that they have independent founders. Although there is no definitive reported geno-phenotype correlation with the abovementioned variant, the results of these two studies are suggestive of the value of further study regarding this correlation.…”