Monogenic and polygenic causes of low and extremely low LDL-C levels in patients referred to specialty lipid clinics: Genetics of low LDL-C.

BACKGROUND: In clinical setting, current standard-of-care does not include genetic testing for patients with low (<50 mg/dL) and extremely low (<20 mg/dL) levels of serum low-density lipoprotein-cholesterol (LDL-C). OBJECTIVE: We aimed identify the underlying molecular cause - both monogenic and polygenic - of low and extremely low LDL-C levels in a cohort of patients presenting to specialty lipid clinics. METHODS: Whole exome sequencing was done in patients with low or extremely low LDL-C not due to any secondary causes. RESULTS: Nine patients (4 women), ranging in age from 25 to 63 years old, with low or extremely low LDL-C levels were evaluated. Median LDL-C was 16 mg/dL (range undetectable - 43), total cholesterol 82 mg/dL (42 - 101), triglycerides 35 mg/dL (19-239), and high-density lipoprotein-cholesterol 45 mg/dL (24-81). Of nine patients, two carried known pathogenic variants in APOB (one stop-gain, one deletion; LDL-C range undetectable -10 mg/dL); three patients had novel APOB heterozygous mutations (two frameshift deletions and one splice site; LDL-C range undectable-13 mg/dL); two had heterozygous APOB frameshift deletions previously reported as variants of unknown significance (LDL-C 18 mg/dL in both patients); one (LDL-C 43 mg/dL) had two heterozygous mutations in PCSK9, both previously reported to be benign; and one patient (LDL-C 16 mg/dL) had the APO E2/E2 genotype along with several variants of unknown significance in genes associated with triglycerides. No patients had an LDL-C polygenic risk score below the 5th percentile (range 26th percentile to 93rd percentile). CONCLUSION: We found APOB mutations to be the most common molecular defect in patients presenting to lipid clinics with low or extremely low LDL-C . Whether clinical genetic testing and LDL-C polygenic risk scores have any utility - other than diagnostic purposes - for such patients remains unclear. In addition, further efforts may be needed to better reclassify pathogenicity of variants of unknown significance.

A high throughput and sensitive method correlates neuronal disorder genotypes to Drosophila larvae crawling phenotypes.

Drosophila melanogaster is widely used as a model system for development and disease. Due to the homology between Drosophila and human genes, as well as the tractable genetics of the fly, its use as a model for neurologic disorders, in particular, has been rising. Locomotive impairment is a commonly used diagnostic for screening and characterization of these models, yet a fast, sensitive and model-free method to compare behavior is lacking. Here, we present a high throughput method to quantify the crawling behavior of larvae. We use the mean squared displacement as well as the direction autocorrelation of the crawling larvae as descriptors of their motion. By tracking larvae from wild-type strains and models of the Fragile X mental retardation as well as Alzheimer disease, we show these mutants exhibit impaired crawling. We further show that the magnitude of impairment correlates with the severity of the mutation, demonstrating the sensitivity and the dynamic range of the method. Finally, we study larvae with altered expression of the shaggy gene, a homolog of Glycogen Synthase Kinase-3 (GSK-3), which has been implicated in Alzheimer disease. Surprisingly, we find that both increased and decreased expression of dGSK-3 lead to similar larval crawling impairment. These findings have implications for the use of GSK-3 inhibitors recently proposed for Alzheimer treatment.