Retinoic acid receptor beta variant‐related colonic hypoganglionosis

Abstract

Present addressGeneDx, Gaithersburg, MD 20877. Retinoic acid receptor beta (RARB) variants are heavily linked to pathologies of neural crest cell migration. The purpose of this report is to present a 23-month-old male with the previously described R387C RARB gain-of-function variant whose gastrointestinal issues and long-term constipation lead to the discovery of colonic hypoganglionosis. This case further delineates the pattern of malformation associated with RARB variants. The findings are also consistent with the known etiology of aganglionic colon due to failed neural crest cell migration. K E Y W O R D Shypoganglionosis, RARB, retinoic acid

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta

“…In addition to the 25 affected individuals with novel variants, we report here 5 new individuals with known variants, including p.(Arg387Cys) (n = 3), p.(Arg387Ser) (n = 1), and p.(Leu213Pro) (n = 1), and we provide additional clinical information about previously described individuals with the variants p.(His291Leu) and p.(Ser398*) (Supplemental Table 1). 13,15 In total, by combining these 32 cases with 20 previously reported ones, 3,4,12,14,[16][17][18][19] we obtained a series of 52 individuals carrying likely pathogenic or pathogenic dominant variants in RARB (total of 26 variants) for whom we have access to some clinical data (Table 1, Supplemental Table 1). Two cases were fetuses from terminated pregnancies and 6 individuals were deceased, including 4 neonatal deaths caused by respiratory failure related to diaphragmatic hernia/eventration and 2 deaths in older children from infections in the context of severe motor impairment.…”

Enzymology and significance of protein histidine methylation

“…Few studies have yet focused on the physiological implications of METTL9 and its links to disease. However, independent genetic studies have linked chromosomal deletion of a segment encompassing METTL9, as well as the IGSF6 and OTOA genes, to colonic hypoganglionosis ( 61 ) and hearing loss ( 62 ).…”