Brachyolmia是一组异质性的发育障碍,其特征是躯干短,身材矮小,脊柱侧弯,长骨无明显畸形的全身性桔梗。DASS(牙齿异常和矮小),由LTBP3基因的改变引起,以前被认为是短裂型血症的一种亚型。本研究调查了三个不相关的近亲家庭(A,B,C)来自埃及和巴基斯坦的Brachyolmia和DASS。在我们的埃及病人身上,我们还观察到听力受损。进行外显子组测序以确定患者中不同临床状况的遗传原因。外显子组测序确定了一种新的纯合剪接受体位点变体(LTBP3:c.3629-1G>T;p。?),负责DASS表型和已知的纯合错义变体(CABP2:c.590T>C;p.Ile197Thr),导致埃及患者的听力障碍。此外,在巴基斯坦患者中发现了两种先前报道的纯合移码变体(LTBP3:c.132delG;p.Pro45Argfs*25)和(LTBP3:c.2216delG;p.Gly739Alafs*7)。这项研究强调了LTBP3在轴向骨骼和牙齿形态发生中的重要作用,并扩展了LTBP3的突变谱。我们报告了三个家庭的七名患者的LTBP3变异,主要导致伴有牙齿和心脏异常的近视症。骨骼评估记录短网状颈部,宽阔的胸部,轻度长骨受累的证据,短的远端指骨,pes平面和骨质疏松性骨纹理作为其他相关发现,扩大了DASS的临床表型。目前的研究表明,A家族埃及患者的听力障碍表型具有独立于LTBP3的独立传播机制。
Brachyolmia is a heterogeneous group of developmental disorders characterized by a short trunk, short stature, scoliosis, and generalized platyspondyly without significant deformities in the long bones. DASS (Dental Abnormalities and Short Stature), caused by alterations in the LTBP3 gene, was previously considered as a subtype of
brachyolmia. The present study investigated three unrelated consanguineous families (A, B, C) with
Brachyolmia and DASS from Egypt and Pakistan. In our Egyptian patients, we also observed hearing impairment. Exome sequencing was performed to determine the genetic causes of the diverse clinical conditions in the patients. Exome sequencing identified a novel homozygous splice acceptor site variant (LTBP3:c.3629-1G > T; p. ?) responsible for DASS phenotypes and a known homozygous missense variant (CABP2: c.590T > C; p.Ile197Thr) causing hearing impairment in the Egyptian patients. In addition, two previously reported homozygous frameshift variants (LTBP3:c.132delG; p.Pro45Argfs*25) and (LTBP3:c.2216delG; p.Gly739Alafs*7) were identified in Pakistani patients. This study emphasizes the vital role of LTBP3 in the axial skeleton and tooth morphogenesis and expands the mutational spectrum of LTBP3. We are reporting LTBP3 variants in seven patients of three families, majorly causing
brachyolmia with dental and cardiac anomalies. Skeletal assessment documented short webbed neck, broad chest, evidences of mild long bones involvement, short distal phalanges, pes planus and osteopenic bone texture as additional associated findings expanding the clinical phenotype of DASS. The current study reveals that the hearing impairment phenotype in Egyptian patients of family A has a separate transmission mechanism independent of LTBP3.