Mine Koprulu, Rana Muhammad Kamran Shabbir, Sara Mumtaz, Aslıhan Tolun, Sajid Malik
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引用次数: 0
Abstract
We present a Pakistani kinship afflicted with a syndrome with features including short stature, reduced sitting height, orofacial symptoms including prominent forehead and thick eyebrows, short and broad thorax, and variable features such as long philtrum, short broad neck, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Phenotypic variation even within different sibships was considerable. The unique combination of the phenotypic characteristics prompted us to determine the shared homozygosity regions in patient genomes and the pathogenic variants by next generation technologies like single nucleotide polymorphism (SNP) genotyping and whole exome sequencing (WES). Through these analyses, we detected homozygous OBSL1 c.848delG (p.Gly283AlafsTer54) as the causal variant. Biallelic variants in OBSL1 are known to cause Three M Syndrome 2 (3M2), a rare disorder of growth retardation with characteristic facial dysmorphism and musculoskeletal abnormalities. Affected members of the family do not have the 3M2 hallmark features of dolichocephaly, hypoplastic midface, anteverted nares, low nasal bridge, pectus excavatum, sacral hyperlordosis, spina bifida occulta, anterior wedging of thoracic vertebrae, prominent heels, and prominent talus. Moreover, they have some variable features not typical for the syndrome such as round face, disproportionate short stature, barrel chest, thoracic kyphoscoliosis, hypogonadism, and hypospadias. Our study facilitated genetic diagnosis in the family, expanded the clinical phenotype for 3M2, and unraveled the considerable clinical variation within the same kinship. We conclude that unbiased molecular analyses such as WES should be more integrated into healthcare, particularly in populations with high parental consanguinity, given the potential of such analyses to facilitate diagnosis.
我们报告一名巴基斯坦亲属患有一种综合征,其特征包括身材矮小、坐高降低、口面症状包括前额突出和眉毛浓密、胸部短而宽,以及多种特征,如人中长、脖子短而宽、桶状胸、胸部后凸、性腺功能减退和尿道下裂。表型变异甚至在不同的同胞体内也是相当大的。表型特征的独特组合促使我们通过单核苷酸多态性(SNP)基因分型和全外显子组测序(WES)等下一代技术来确定患者基因组和致病性变体中的共享纯合子区域。通过这些分析,我们检测到纯合的OBSL1 c.848delG(p.Gly283AlafsTer54)是致病变体。已知OBSL1的双等位基因变异会导致Three M Syndrome 2(3M2),这是一种罕见的生长迟缓疾病,具有特征性的面部畸形和肌肉骨骼异常。受影响的家族成员没有3M2的标志性特征,如小头畸形、面中部发育不全、鼻孔前倾、低鼻梁、漏斗胸、骶骨前凸、隐性脊柱裂、胸椎前楔入、突出的跟部和突出的距骨。此外,他们有一些不典型的综合征的可变特征,如圆脸、不成比例的矮小、圆胸、胸部后凸畸形、性腺功能减退和尿道下裂。我们的研究促进了该家族的基因诊断,扩大了3M2的临床表型,并揭示了同一亲缘关系中相当大的临床变异。我们的结论是,考虑到此类分析有助于诊断的潜力,WES等无偏见的分子分析应更多地纳入医疗保健,特别是在父母血亲较高的人群中。
期刊介绍:
The Yale Journal of Biology and Medicine (YJBM) is a graduate and medical student-run, peer-reviewed, open-access journal dedicated to the publication of original research articles, scientific reviews, articles on medical history, personal perspectives on medicine, policy analyses, case reports, and symposia related to biomedical matters. YJBM is published quarterly and aims to publish articles of interest to both physicians and scientists. YJBM is and has been an internationally distributed journal with a long history of landmark articles. Our contributors feature a notable list of philosophers, statesmen, scientists, and physicians, including Ernst Cassirer, Harvey Cushing, Rene Dubos, Edward Kennedy, Donald Seldin, and Jack Strominger. Our Editorial Board consists of students and faculty members from Yale School of Medicine and Yale University Graduate School of Arts & Sciences. All manuscripts submitted to YJBM are first evaluated on the basis of scientific quality, originality, appropriateness, contribution to the field, and style. Suitable manuscripts are then subject to rigorous, fair, and rapid peer review.