A novel proximal 3q29 chromosome microdeletion in a Chinese patient with Chiari malformation type II and Sprengel’s deformity

Abstract

BackgroundChiari malformation type II (CM-II) is mainly characterized by elongation and descent of the cerebellum through the foramen magnum into the spinal canal. Moreover, CM-II is uniquely associated with myelomeningocele. Sprengel’s deformity refers to the malposition of the scapula, i.e. scapular elevation which is sometimes accompanied with scapula dysplasia. Although few familial cases of CM-II and Sprengel’s deformity have been previously reported, both of these defects are considered to be sporadic, thus the exact etiology and causative genes have largely remained unknown.Case presentationThe patient was diagnosed with CM-II accompanied with Sprengel’s deformity. Further genetic investigation revealed a novel 666 kb microdeletion located in 3q29 (chr3:194,532,035–195,198,585; Hg19). Subsequently, genes within the affected region were summarized, and XXYLT1 and ACAP2 were identified as the candidate genes.ConclusionWe reported a case of a patient with CM-II and Sprengel’s deformity harboring a microdeletion in 3q29. This case highlights the importance of 3q29 in early neural and skeletal development, as well as expands the phenotype spectrum of this rare disorder.

Prenatal detection of a 3q29 microdeletion in a fetus with ventricular septum defect

“…Till now, cases with 3q29 microdeletion are rarely reported in clinic. [ 6 – 8 , 12 ] Considering the unusual cardiac defect discovered in such cases, we reviewed the literature and made a comparison on 3q29 microdeletion cases presenting cardiac anomalies to delineate the phenotype-karyotype correlations clearly (Table 1 ). [ 7 , 13 – 18 ] All 3q29 microdeletions varied in size, from 0.96 Mb to 1.6 Mb.…”

“…In addition, some rare anomalies involving neural and skeletal development have been reported in some cases. Guo et al [ 12 ] described a 7-year-old girl with Chiari malformation type II and Sprengel's deformity, accompanied by a novel 666 kb microdeletion in 3q29 (chr3:194,532,035–195,198,585; hg19). Since the couple in our study did not accept SNP array, we fail to confirm the deletion was de novo or inherited.…”

“…It was speculated that XXYLT1 dysfunction due to 3q29 microdeletion might impair epidermal growth factor (EGF) xylosylation, leading to up-regulated Notch signaling. [ 12 , 21 ] Human amplification of XXYLT1 in several kinds of cancer is frequently associated with decreased Notch signaling. [ 22 ] ACAP2 (OMIM: 607766), is an Arf-6 GTPase-activating protein which can inactivate Arf6 at the pericentrosomal endosomes and regulate neurite outgrowth.…”

C3orf21 and Notch Signaling in Cancer：A Potential Biomarker

“…There are 36 tandem EGF-like repeats in the Notch extracellular domain [25], they were modified by O-linked fucose, glucose, or N-acetylglucosamine (GlcNAc) [26]. Notch activation is modulated by the differential O-linked glycosylation of its extracellular domain (NECD) [20], whereby O-linked glucose is added to a subset of EGF repeats in the NECD domain by Protein O-glucosyltransferase 1 (POGLUT1) [5,27,28]. This can be subsequently extended to xylose α1-3 glucose trisaccharide by the sequential action of Glucoside α1-3 xylosyl transferase (GXYLT1/2) [17] and xyloside α1-3 xylosyl transferase (XXYLT1) [29].…”

“…Notch signaling activation is modulat-microduplication syndrome region including XXYLT1 was associated to Oculo auriculo vertebral specturm [19]. XXYLT1 microdeletion also was associated with Chiari malformation type II [20]. In addition, the XXYLT1 rs9825174 polymorphism was associated with associated with osteoporosis and obesity [21], and C3orf21 rs2720932 was associated with systemic lupus erythematosus (SLE) in the Korean population [22].…”