Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-02-17 , DOI: 10.1038/s41436-020-01075-9
Agustí Rodríguez-Palmero 1, 2 , Melissa Maria Boerrigter 3, 4 , David Gómez-Andrés 5 , Kimberly A Aldinger 6 , Íñigo Marcos-Alcalde 7, 8 , Bernt Popp 9, 10 , David B Everman 11 , Alysia Kern Lovgren 12 , Stephanie Arpin 13 , Vahid Bahrambeigi 11, 14 , Gea Beunders 15 , Anne-Marie Bisgaard 16 , V A Bjerregaard 3 , Ange-Line Bruel 17 , Thomas D Challman 18 , Benjamin Cogné 19, 20 , Christine Coubes 21 , Stella A de Man 22 , Anne-Sophie Denommé-Pichon 17 , Thomas J Dye 23, 24 , Frances Elmslie 25 , Lars Feuk 26 , Sixto García-Miñaúr 27 , Tracy Gertler 28 , Elisa Giorgio 29 , Nicolas Gruchy 30 , Tobias B Haack 31 , Chad R Haldeman-Englert 32 , Bjørn Ivar Haukanes 33 , Juliane Hoyer 9 , Anna C E Hurst 34 , Bertrand Isidor 19, 20 , Maria Johansson Soller 35, 36 , Sulagna Kushary 37 , Malin Kvarnung 35, 36 , Yuval E Landau 38, 39, 40 , Kathleen A Leppig 41 , Anna Lindstrand 35, 36 , Lotte Kleinendorst 42 , Alex MacKenzie 43 , Giorgia Mandrile 44 , Bryce A Mendelsohn 45 , Setareh Moghadasi 46 , Jenny E Morton 47 , Sebastien Moutton 17, 48 , Amelie J Müller 31 , Melanie O'Leary 12 , Marta Pacio-Míguez 27 , Maria Palomares-Bralo 27 , Sumit Parikh 49 , Rolph Pfundt 50 , Ben Pode-Shakked 40, 50, 51, 52 , Anita Rauch 53 , Elena Repnikova 54 , Anya Revah-Politi 36, 55 , Meredith J Ross 56 , Claudia A L Ruivenkamp 46 , Elisabeth Sarrazin 57 , Juliann M Savatt 18 , Agatha Schlüter 1 , Bitten Schönewolf-Greulich 3 , Zohra Shad 58 , Charles Shaw-Smith 59 , Joseph T Shieh 60 , Motti Shohat 61 , Stephanie Spranger 62 , Heidi Thiese 41 , Frederic Tran Mau-Them 17 , Bregje van Bon 63 , Ineke van de Burgt 63 , Ingrid M B H van de Laar 64 , Esmée van Drie 42 , Mieke M van Haelst 42 , Conny M van Ravenswaaij-Arts 15 , Edgard Verdura 1 , Antonio Vitobello 17 , Stephan Waldmüller 31 , Sharon Whiting 43 , Christiane Zweier 9 , Carlos E Prada 24, 65 , Bert B A de Vries 63 , William B Dobyns 6, 66, 67 , Simone F Reiter 33 , Paulino Gómez-Puertas 7 , Aurora Pujol 1, 68 , Zeynep Tümer 3, 69
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Purpose
Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.
Methods
The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.
Results
The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.
Conclusion
The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
中文翻译:

DLG4相关突触病:一种新的罕见脑部疾病
目的
由DLG4编码的突触后密度蛋白 95 (PSD-95)调节大脑中的兴奋性突触功能。在这里,我们介绍了 53 名患有DLG4变体的患者(42 名以前未发表过)的临床和遗传特征。
方法
临床和遗传信息是通过 GeneMatcher 合作收集的。所有个体均由当地临床医生进行调查,并通过临床外显子组/基因组测序鉴定基因变异。
结果
临床表现主要是早发性全球发育迟缓、智力障碍、自闭症谱系障碍和注意力缺陷多动障碍,所有这些都指向脑部疾病。Marfanoid 习性,以前被认为是DLG4相关表型的特征,仅在 9 个人中发现,尽管有一些重叠的特征,但无法确定明显的面部畸形。在 45 种不同的DLG4变体中,预计 39 种会导致蛋白质功能丧失,并且大多数是从头发生的(四种来源不明)。蛋白质建模研究表明,鉴定出的六种错义变体会导致结构或功能变化。
结论
本研究表明,与DLG4相关的临床表现与在其他突触功能障碍的神经发育障碍中发现的临床表现重叠;因此,我们将这组疾病称为DLG4相关突触病。