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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.
摘要：
我们提出了一个巴基斯坦亲属患有一种综合症，其特征包括身材矮小，降低坐姿高度,口面部症状包括突出的前额和浓密的眉毛，胸部又短又宽，和可变的特征，如长hiltrum，短而宽的脖子,桶状胸部,胸椎脊柱后凸,性腺功能减退,和尿道下裂.即使在不同的同胞中，表型变异也相当大。表型特征的独特组合促使我们通过下一代技术如单核苷酸多态性(SNP)基因分型和全外显子组测序(WES)来确定患者基因组中的共有纯合性区域和致病变体。通过这些分析,我们检测到纯合OBSL1c.848delG（p。Gly283AlafsTer54)作为因果变体。已知OBSL1中的双等位基因变体会导致三M综合征2（3M2），一种罕见的生长迟缓症，具有特征性面部畸形和肌肉骨骼异常。受影响的家庭成员没有dolichocephaly的3M2标志特征，面部发育不全,前vertednares，低鼻梁，漏斗胸,骶骨过度前凸,隐性脊柱裂,胸椎前楔入，突出的高跟鞋，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，不成比例的身材矮小，桶状胸部,胸椎脊柱后凸,性腺功能减退,和尿道下裂.我们的研究促进了家庭的基因诊断，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。我们得出的结论是，诸如WES之类的无偏分子分析应该更多地整合到医疗保健中，特别是在父母血缘关系很高的人群中，考虑到此类分析有助于诊断的潜力。
