Abstracts

Rationale: With the advantage of detecting copy number variations (CNVs) and intronic variants whole genome sequencing (WGS) has been applied more widely in genetic diagnosis. However, due to the short reads, current WGS is still limited in detecting large fragment structural variations (SV) and oligonucleotide repeat expansion. Here we reported a family for which a novel DYNC1H1 missense variant was detected in both the son with lissencephaly presenting by Lennox-Gastaut syndrome and developmental delay with intellectual disability (DDID) and the father who had mild dementia only but no epilepsy or brain malformation. Therefore, we submitted both the son and his father for Pacbio long-read WGS (L-WGS) to search for the other genomic modifying factors of the phenotype.


Methods: We first performed short-read WGS for the proband and detected a novel heterozygous variant: DYNC1H1:c.9709 A >G: p.Asn3237Asp. Sanger sequencing confirmed the variant is inherited from the father and shared by his brother with the same phenotype. According to the 2015 ACMG guideline, the variant is likely pathogenic. The patient and his father were then submitted for PacbioL-WGS.

Results: This 32-year-old man is a patient of Lennox-Gastaut syndrome with the seizure onset before 1 year old. He received vagus nerve stimulation (VNS) for drug-resistant epilepsy (DRE). He also has been noted to have DDID. After the teenage, he started to have some involuntary movements, including orobuccal dyskinesia and dystonia/tremor of bilateral upper limbs. Brain MRI showed diffuse pachygyria, compatible with lissencephaly. His junior brother is also a patient of DRE and DDID. Brain MRI showed mild pachygyria, too. Both parents denied a history of epilepsy. However, their father was diagnosed as mild dementia in the early of 50s (MMSE=22). His brain MRI showed mild generalized atrophy only, without pachygyria. L-WGS identified a large deletion in chromosome X which contains the gene for lissencephaly, DCX, which the son harbored, but not the father.


Conclusions: This study provided the example that intrafamilial variation of the phenotype may be contributed by additional pathogenic genomic variations or genomic modifiers of the phenotype. L-WGS is a powerful tool for detecting large fragment SV and other genomic modifiers.


Funding: National Science and Technology Council NSTC 113-2314-B-075-078-