PURPOSE: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified. METHODS: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached. RESULTS: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others. CONCLUSION: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.

• MeSH
• genetická variace genetika   MeSH
• genetické testování metody   MeSH
• genom lidský * genetika   MeSH
• genomika metody   MeSH
• hyperlipoproteinemie typ II * genetika   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Stalk lodging, which is generally determined by stalk strength, results in considerable yield loss and has become a primary threat to maize (Zea mays) yield under high-density planting. However, the molecular genetic basis of maize stalk strength remains unclear, and improvement methods remain inefficient. Here, we combined map-based cloning and association mapping and identified the gene stiff1 underlying a major quantitative trait locus for stalk strength in maize. A 27.2-kb transposable element insertion was present in the promoter of the stiff1 gene, which encodes an F-box domain protein. This transposable element insertion repressed the transcription of stiff1, leading to the increased cellulose and lignin contents in the cell wall and consequently greater stalk strength. Furthermore, a precisely edited allele of stiff1 generated through the CRISPR/Cas9 system resulted in plants with a stronger stalk than the unedited control. Nucleotide diversity analysis revealed that the promoter of stiff1 was under strong selection in the maize stiff-stalk group. Our cloning of stiff1 reveals a case in which a transposable element played an important role in maize improvement. The identification of stiff1 and our edited stiff1 allele pave the way for efficient improvement of maize stalk strength.

• MeSH
• alely MeSH
• buněčná stěna metabolismus   MeSH
• CRISPR-Cas systémy MeSH
• fenotyp MeSH
• kukuřice setá genetika   MeSH
• lignin metabolismus   MeSH
• lokus kvantitativního znaku MeSH
• mapování chromozomů MeSH
• promotorové oblasti (genetika) * MeSH
• rostlinné geny MeSH
• rostlinné proteiny genetika   metabolismus   MeSH
• sekvenční analýza MeSH
• transformace genetická MeSH
• transpozibilní elementy DNA genetika   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sweet maize and popcorn retain tillering growth habit during maize diversification. However, the underlying molecular genetic mechanism remains unknown. Here, we show that the retention of maize tillering is controlled by a major quantitative trait locus (QTL), tin1, which encodes a C2H2-zinc-finger transcription factor that acts independently of tb1. In sweet maize, a splice-site variant from G/GT to C/GT leads to intron retention, which enhances tin1 transcript levels and consequently increases tiller number. Comparative genomics analysis and DNA diversity analysis reveal that tin1 is under parallel selection across different cereal species. tin1 is involved in multiple pathways, directly represses two tiller-related genes, gt1 and Laba1/An-2, and interacts with three TOPLESS proteins to regulate the outgrowth of tiller buds. Our results support that maize tin1, derived from a standing variation in wild progenitor teosinte population, determines tillering retention during maize diversification.

• MeSH
• fenotyp MeSH
• genetické lokusy MeSH
• kukuřice setá genetika   růst a vývoj   metabolismus   MeSH
• lokus kvantitativního znaku MeSH
• regulace genové exprese u rostlin MeSH
• rostlinné geny genetika   MeSH
• rostlinné proteiny genetika   metabolismus   MeSH
• vývoj rostlin genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH