A de novo 0.63 Mb 6q25.1 deletion associated with growth failure, congenital heart defect, underdeveloped cerebellar vermis, abnormal cutaneous elasticity and joint laxity

Abstract

Deletions of the long arm of chromosome 6 are rare and are characterized by great clinical variability according to the deletion breakpoint. We report a on 6-year-old girl with a de novo 0.63 Mb deletion on chromosome 6q25.1 who demonstrated multiple congenital anomalies including a ventricular septal defect and an underdeveloped cerebellar vermis. She presented with severe pre- and post-natal growth failure, hyperextensible small joints (Beighton scores = 8/9; with normal parental scores), and an abnormally elastic, redundant skin. Abnormally high upper/lower segment ratio (i.e., 1.34 = > 3SD), mild dysmorphic facial features and developmental delay were also present. The girl's phenotype was compared with: (i) two girls, each previously reported by Bisgaard et al. and Caselli et al. with similar albeit larger (2.6-7.21 Mb) deletions; (ii) seven additional individuals (6 M; 1 F) harboring deletions within the 6q25.1 region reported in the literature; and (iii) ten further patients (5 M; 4 F; 1 unrecorded sex) recorded in the DECIPHER 6.0 database. We reported on the present girl as her findings could contribute to advance the phenotype of 6q deletions. In addition, the present deletion is the smallest so far recorded in the 6q25 region encompassing eight known genes [vs. 41 of Bisgaard et al., and 23 of Caselli et al.,], including the TAB2 (likely responsible for the girl's congenital heart defect), LATS1 gene, and the UST gene (a regulator of the homeostasis of proteoglycans, which could have played a role in the abnormal dermal and cartilage elasticity).

A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations

“…Previously published and present patients with TAB2 variants or chromosome deletions, defined by cytogenetic‐molecular tools and encompassing TAB2 , are reported in Table . Twenty‐two patients were identified with a highly variable phenotype, ranging from isolated CHD to systemic conditions with multiple malformations and intellectual disability/global developmental delay . Genotype‐phenotype correlations are incomplete.…”

“…Recently, a TAB2 nonsense variant was reported in a sporadic patient with complex CHD, facial dysmorphism and myopia . A 6q25.1 deletion encompassing TAB2 was also identified in a 3‐generation family with apparently isolated cardiac valve dysplasia and tetralogy of Fallot, as well as in a sporadic patient with multiple cardiac valve dysplasia, soft skin, joint hypermobility, unusual face, short limbs and stature . Finally, an apparently different phenotype, consistent with frontometaphyseal dysplasia (FMD), was identified in a patient with a TAB2 missense variant …”

Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase

“…CHO-K1 cells express Ust which subsequently leads to CS/DS 2-O sulfation, later involved in Fgf-2-induced migration [5]. Recently, a patient with a microdeletion on chromosome 6q25.1 was described with among other symptoms an Ehlers-Danlos syndrome in skin [45]. The microdeletion included the lack of human UST gene indicating that the minor sulfation of CS/DS affects also the organization of the extracellular matrix, similar to the DS [46].…”

“…Of note, B16 cells contain 1.5 times more DS than LCC cells [18] indicating that adhesion and migration of melanoma cells could be influenced by 2-O sulfated CS/DS. Under physiological conditions, Ust has been shown to be important for in vivo cell migration and possibly development [19, 45]. …”

Pathophysiological Significance of Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders

“…A de novo 0.63 Mb deletion on chromosome 6q25.1 causes multiple congenital anomalies such as developmental delay, mild dysmorphic facial features, abnormally elastic and redundant skin, hyperextensible small joints, ventricular septal defect, and underdeveloped cerebellar vermis [59]. This region contains eight genes including UST , TAB2 , and LATS1 .…”