Saida Ken, Fukuda Tokiko, Scott Daryl A, Sengoku Toru, Ogata Kazuhiro, Nicosia Annarita, Hernandez-Garcia Andres, Lalani Seema R, Azamian Mahshid S, Streff Haley, Liu Pengfei, Dai Hongzheng, Mizuguchi Takeshi, Miyatake Satoko, Asahina Miki, Ogata Tsutomu, Miyake Noriko, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Front Cell Dev Biol. 2021 Mar 3;9:631428. doi: 10.3389/fcell.2021.631428. eCollection 2021.
X-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic variants, was recently reported as a new XLID with additional congenital anomalies.
We investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.
A hemizygous missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.
Unlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.
X连锁智力障碍（XLID）主要发生于男性，是一种相对常见的、具有遗传异质性的疾病，目前已报道100多个突变基因。位于Xp11.23的基因编码卵巢肿瘤去泛素酶5蛋白，它是卵巢肿瘤家族的一种去泛素化酶成员。最近有报道称，由致病性变异引起的连锁特异性去泛素化缺陷诱导的胚胎缺陷（LINKED）综合征是一种新的XLID，伴有其他先天性异常。
我们对来自两个家庭的三名患病男性（49岁和47岁的兄弟[个体1和个体2]以及一名2岁男孩[个体3]）进行了调查，他们均表现出发育迟缓。他们共同的临床特征包括发育迟缓、肌张力减退、身材矮小以及独特的面部特征，如眼距增宽和鼻梁凹陷。个体1和个体2患有癫痫，脑部磁共振成像显示胼胝体变薄和轻度脑室扩大。个体3有先天性畸形，包括法洛四联症、尿道下裂和双侧隐睾。为了确定这些特征的遗传原因，我们进行了全外显子组测序。
在有个体1和个体2的一个家庭中，发现了一个半合子错义变异，c.878A>T，p.Asn293Ile [NM_017602.4]；在有个体3的另一个家庭中，发现了另一个错义变异，c.1210 C>T，p.Arg404Trp。前一个变异未在公共数据库中登记，多种预测工具预测其具有致病性。后一个变异p.Arg404Trp先前已被报道为致病性变异，个体3表现出典型的LINKED综合征表型。然而，携带新变异（p.Asn293Ile）的个体1和个体2没有心脏或泌尿生殖系统畸形。
与之前报道的LINKED综合征（描述为伴有先天性心脏异常的早期致死性）不同，我们的三例患者仍然存活。值得注意的是，携带新错义变异的成年兄弟已活到四十多岁。这可能表明一种较轻的表型，提示可能存在基因型-表型相关性。这些发现意味着这种新的XLID综合征患者可能有长期预后，且表型变异比最初认为的更广泛。
