The most 5′ truncating homozygous mutation of WNT1 in siblings with osteogenesis imperfecta with a variable degree of brain anomalies: a case report

Abstract

BackgroundWNT1 mutations cause bone fragility as well as brain anomalies. There are some reported cases of WNT1 mutations with normal cognition. Genotype and phenotype correlation of WNT1 mutations has not been established.Case presentationHere we present two female siblings with osteogenesis imperfecta (OI) born to a consanguineous couple. Both sustained severe bone deformities. However, only the younger had severe brain anomalies resulting in an early death from pneumonia, while the older had normal intellectual development. Next generation sequencing showed a homozygous mutation, c.6delG, p.Leu3Serfs*36 in WNT1. To our knowledge, it is the most 5′ truncating mutation to date.ConclusionThis report emphasizes the intrafamilial variability of brain anomalies found in this OI type and suggests that WNT1 may not be necessary for normal human cognitive development.

Ptosis as a unique hallmark for autosomal recessive WNT1‐associated osteogenesis imperfecta

“…Bluish sclerae were not observed in our patient cohort, but have been noted in a few patients with bi‐allelic‐ WNT1 mutations (9/34, 26.5%; Supporting Information Table S1). Hearing and tooth development are usually not impaired (Aldinger et al, ; Fahiminiya et al, ; Faqeih et al, ; Keupp et al, ; Kuptanon et al, ; Laine et al, ; Lu et al, ; Pyott et al, ; Umair et al, ; Won et al, ).…”

“…The cause of ptosis is currently unknown. It has been noted that some patients with bi‐allelic WNT1 mutations have neurological/brain abnormalities (6/11, 54.5%), including abnormalities of the midbrain and/or cerebellum, and/or severe developmental/intellectual delay (11/28, 39.3%; Aldinger et al, ; Fahiminiya et al, ; Faqeih et al, ; Keupp et al, ; Kuptanon et al, ; Laine et al, ; Lu et al, ; Pyott et al, ; Umair et al, ; Won et al, ). Brain images for our cohort were available for only one patient (PVIII, presenting with severe brain anomalies, Figure v) and four patients had a significant delay in cognitive development (4/10, 40%).…”

“…Homozygous and compound heterozygous mutations in WNT1 have been identified in a series of patients displaying moderate to severe AR forms of OI (compatible with OI type III or IV according to the Sillence classification; Aldinger et al, ; Fahiminiya et al, ; Faqeih, Shaheen, & Alkuraya, ; Keupp et al, ; Kuptanon et al, ; Laine et al, ; Lu et al, ; Pyott et al, ; Umair et al, ; Won et al, ). This type of OI is currently classified as OI type XV (Forlino & Marini, ; Kang et al, ; Marini et al, ; Sillence, Senn, & Danks, ).…”

Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene

“…WNT1 pathogenic variants impair b-Catenin translocation affecting osteoblast function and peak bone mass (28,29). WNT1 pathogenic variants described so far (Figure 3) are associated with different pictures of bone fragility according to whether the variant was heterozygous or homozygous (13)(14)(15)(16)(17)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). In fact, patients carrying heterozygous variants exhibit normal growth, reduced bone mass or early-onset osteoporosis and fractures without appendicular deformities (13-15, 42) (Table 3), whereas those carrying homozygous variants display a life-threatening phenotype due to severe bone deformities (12)(13)(14)19).…”

MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders

“…Over the past decade, however, the advent of high-resolution sequencing technologies such as next-generation sequencing (NGS) and the increased application of whole-exome sequencing has greatly widened the horizon of the genetic contributions to OI. These approaches have led to the identification of new OI-causing genes and novel pathogenic variants that are not classically associated with collagen metabolism and can occur via distinct inheritance patterns, such as the first X-linked recessive form of OI (OI type XIX, OI19, MIM #301014), caused by missense mutations in MBTPS2 [ 3 , 120 , 121 ] (Fig. 3 c, d).…”