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Another great year contributing and sharing at ACMG 2018 in Charlotte, NC

April 26, 2018
It was great to see many of our existing Lineagen partners and meeting new ones at ACMG this year. We hope you enjoyed Lineagen’s happy hour event and learned more about our scientific contributions from our poster presentations. If you didn’t get a chance to join us in Charlotte, we have summarized the posters below. We will see you at the next scientific and clinical conference related to neurodevelopmental disorders!
 
Noncoding and Copy Number Variants Solve Multiple Undiagnosed Diseases Network (UDN) Mysteries
The Undiagnosed Disease Network (UDN) is a research study backed by the National Institutes of Health Common Fund that seeks to provide answers for individuals and families with unexplained medical conditions. The UDN sought to determine the contribution of noncoding variants and copy number variants to the first 30 UDN patients that received diagnoses at the Vanderbilt center. One of these children is a girl with a complex medical picture including developmental delay, muscle weakness, seizures, and intellectual disability. She was found to have a de novo (not inherited) deletion of the ZC4H2 gene causing Wieacker-Wolff syndrome on Lineagen FirstStepDX plus chromosomal microarray analysis (CMA). This deletion was not reported on a different CMA, whole exome sequencing, or whole genome sequencing, highlighting the importance of CMA, and specifically the technology and interpretation process at Lineagen.
 
Copy Number Variants Underlying Neurodevelopmental Disorders Provide Insights into Sleep Disorder Genetics
We care about the quality of life of the families we provide testing for. Chromosomal copy number variants (CNVs) can have an impact on brain and central nervous system development, leading to neurodevelopmental disorders; however, sleep disorders which have a huge impact on quality of life have been less studied in relation to CNVs. To investigate this, we combed our database for pathogenic CNVs reported in individuals with sleep disorders and determined the smallest region of overlap for these individuals in order to generate candidate genes. Both the GJA5 gene and HNF1B gene may be important for sleep regulation and are within the same network as other sleep-related genes. Additional research in this realm may lead to better treatment and management considerations for individuals with sleep disorders.
 
The Role of CHL1 Copy Number Variations in Neurodevelopmental Disorders
The CHL1 gene has been of particular interest to Lineagen as it is identified by our proprietary Variant Index database as suspected to be involved in neurodevelopment. We have also noted that we have reported many CNVs involving this gene. Literature review yields conflicting information as it has been proposed as a candidate gene for intellectual disability in 3p deletion syndrome and CNVs of this gene have been reported in at least 21 symptomatic individuals in the medical literature, but CNVs involving this gene lack enrichment in large case-control studies. To further investigate this gene, retrospective analysis of individuals with FirstStepDX Plus chromosome microarray analysis was performed and 31 individuals with a deletion or duplication involving the CHL1 gene were identified. These individuals had overlapping symptoms, with speech and language deficits and developmental delay/intellectual disability being predominant, supporting previous work that CHL1 CNVs are involved in neurodevelopment.
 
The Role of ZDHHC15 in Neurocognitive Disorders and Epilepsy
With a focus on neurodevelopmental conditions, Lineagen is always looking for information on new candidate genes in this realm. FirstStepDX Plus chromosome microarray analysis was performed in 22,847 individuals with neurodevelopmental indications, revealing 15 gains involving the ZDHHC15 gene on the X chromosome. Very little information is known about this gene and there have been no reports in the medical literature describing other individuals with similar gains. Genes located on the X chromosome are challenging to assess for possible pathogenicity due to skewed X inactivation in females and hemizygosity in males. However, based on high expression of this gene in the brain, similar symptoms between these 15 individuals, and rarity of similar gains in unaffected individuals suggest XDHHC15 is another candidate gene for neurocognitive and epilepsy disorders. Identifying individuals with gains in this region could have significant long term medical and developmental impact with respect to seizure surveillance and early intervention of developmental services.
 
A Novel Methylation Assay May Provide Increased Sensitivity: Trial in 311 Patients Referred for Fragile X Testing
Fragile X syndrome is the largest single gene contributor to inherited forms of intellectual disability and autism spectrum disorder, therefore it is important to be able to identify people with this condition. The current testing protocol involves a stepwise process of first determining CGG repeat size (screening step) followed by FMR1 promoter methylation (diagnostic step). We compared the standard testing protocol to methylation specific quantitative melt analysis (MS-QMA) which examines DNA methylation of 12 CpG sites at a different location on the FMR1 gene called FREE2. MS-QMA was performed on extracted DNA from buccal samples of 221 males and 90 females that had neurodevelopmental features and previously had testing for fragile X syndrome using the standard protocol. The MS-QMA methodology identified 12 patients (4.1% of males and 3.3% of females) with abnormal FMR1 methylation that were missed by standard protocol. The results of this study suggests that the commonly utilized testing strategy of screening for methylation analysis by CGG trinucleotide repeat number may miss patients who have features of fragile X syndrome. Because early detection and management of fragile X syndrome is critical to patient care and outcomes, critical evaluation of current testing strategies should be done to ensure optimal sensitivity.
 
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