bioRxiv Science⌕ Search

Biology subjects

Holly K Tabor

Publications and source records attributed to Holly K Tabor.

2 recordsLinked to original sources
bioRxiv2015

Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Purpose:The pace of Mendelian gene discovery is slowed by the \"n-of-1 problem\" - the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.\n\nMethods:Social networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.\n\nResults:De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.\n\nConclusion:Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP). Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

Genetics↗
bioRxiv2015

De novo Mutations in NALCN Cause a Syndrome of Congenital Contractures of the Limbs and Face with Hypotonia, and Developmental Delay

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five simplex cases putatively diagnosed with \"DA2A with severe neurological abnormalities\" in which the proband had Congenital Contractures of the LImbs and FAce, Hypotonia, and global Developmental Delay often resulting in early death, a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in sodium leak channel, nonselective (NALCN) in four families with CLIFAHDD syndrome. Using molecular inversion probes to screen NALCN in a cohort of 202 DA cases as well as concurrent exome sequencing of six other DA cases revealed NALCN mutations in ten additional families with \"atypical\" forms of DA. All fourteen mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that mutant NALCN nearly abolished the expression of wildtype NALCN, suggesting that mutations that cause CLIFAHDD syndrome have a dominant negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families with an autosomal recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition with varied though overlapping phenotypic features perhaps depending on the type of mutation and affected protein domain(s).

Genetics↗