Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels

Abstract

Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis.

Mesenchymal stromal cells from people with osteoporosis are fewer, and defective in both osteogenic and adipogenic capacity

“…Genes with both q < 0.05 from batch analysis and P < 0.05 from individual analysis. These were classified according to pre-defined OP-relevant functions based on literature review (osteogenesis: AJAP1 [52], P2RY6 [37], PRKG1 [53], EFNB2 and EPHB6 [54], HAUS5 [55], MASP1 [56], FAM193B [57], PTDGS [58]; cellular differentiation: TRIT1 [59]; proliferation: ZNF555 [60], TEP1 [61], UBXN8 [62]; cell membrane: NHS [63], ARHGAP32 [64]; neuromuscular function: NEFL [65]). ↑: increased expression in OP; ↓: decreased expression in OP; qval: q value, i.e., corrected P value; DE: differential expression…”