Kyian Tatiana, Borovikov Artem, Anisimova Inga, Ryzhkova Oksana, Bulakh Maria, Bragina Elizabeth, Avakyan Maria, Demchenko Anna, Zabnenkova Victoria, Kovalev Victor, Bukhonin Artem, Kondratyeva Elena, Kutsev Sergey
Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskiye Gory, 1, Build. 40, 119991 Moscow, Russia.
Genes (Basel). 2024 Dec 20;15(12):1633. doi: 10.3390/genes15121633.
Pathogenic variants in the gene are linked to a spectrum of syndromes that exhibit partial clinical overlap. Hemizygous loss-of-function variants are considered lethal in males, while heterozygous loss-of-function variants generally result in oro-facial-digital syndrome type 1. A reported phenotype, Simpson-Golabi-Behmel syndrome type 2, was published once but remains controversial, with many specialists questioning its validity and arguing about its continued listing in the OMIM database.
To investigate the genetic and phenotypic characteristics of the patients, we performed clinical exome sequencing, family-based genetic analysis, X-inactivation studies, electron microscopy, and detailed clinical assessments.
Three patients from unrelated families carrying loss-of-function variants in the gene were identified, emphasizing the diverse phenotypic spectrum of -associated disorders. The first patient, a female with a heterozygous frameshift variant p.(Gln398LeufsTer2), was diagnosed with oro-facial-digital syndrome type 1. The second patient, a male with a heterozygous nonsense variant p.(Gln892Ter), presented with features resembling Simpson-Golabi-Behmel syndrome type 2, as previously reported under this diagnosis. The third patient, a male with another heterozygous nonsense variant p.(Glu879Ter), exhibited isolated primary ciliary dyskinesia without any syndromic features.
This study contributes to the growing body of evidence on the expanding phenotypic spectrum of -associated disorders. It underscores the need for further investigation into the molecular mechanisms underlying the diverse presentations and the necessity of re-evaluating diagnostic classifications for conditions such as SGBS2 in the context of variants in the gene.
该基因中的致病变异与一系列临床表现部分重叠的综合征相关。半合子功能丧失变异被认为对男性是致命的，而杂合子功能丧失变异通常会导致1型口面指综合征。一种已报道的表型，即2型辛普森-戈拉比-贝梅尔综合征，仅发表过一次，但仍存在争议，许多专家质疑其有效性，并就是否应继续列入OMIM数据库展开争论。
为了研究患者的遗传和表型特征，我们进行了临床外显子组测序、基于家系的遗传分析、X染色体失活研究、电子显微镜检查以及详细的临床评估。
我们鉴定出了来自三个无关家系的携带该基因功能丧失变异的患者，这凸显了与该基因相关疾病的表型谱的多样性。第一名患者是一名女性，携带杂合移码变异p.(Gln398LeufsTer2)，被诊断为1型口面指综合征。第二名患者是一名男性，携带杂合无义变异p.(Gln892Ter)，表现出类似于2型辛普森-戈拉比-贝梅尔综合征的特征，此前曾在此诊断下报道过。第三名患者是一名男性，携带另一个杂合无义变异p.(Glu879Ter)，表现为孤立的原发性纤毛运动障碍，无任何综合征特征。
本研究为与该基因相关疾病不断扩大的表型谱提供了更多证据。它强调了进一步研究不同表现背后分子机制的必要性，以及在该基因变异背景下重新评估诸如SGBS2等疾病诊断分类的必要性。
