Cong Yan, Wu Jie, Wang Hao, Wu Ke, Huang Cui, Yang Xuejian
Rehabilitation Department, Yiwu Maternity and Child Health Care Hospital, Yiwu, China.
Prenatal Diagnosis Center, Yiwu Maternity and Child Health Care Hospital, Yiwu, China.
Front Pediatr. 2022 Apr 4;10:834087. doi: 10.3389/fped.2022.834087. eCollection 2022.
Alpha-thalassemia/intellectual disability syndrome (ATR-X) (OMIM # 301040) was first described by Wilkie et al. (1). Several studies found that children who presented with significantly consistent clinical phenotypes of hemoglobin H (Hb H) disease and profound mental handicap carried (, OMIM300032) gene variants. With the recent development of exome sequencing (ES), gene variants of severe to profound intellectual disability without alpha-thalassemia have been implicated in intellectual disability-hypotonic facies syndrome, X-linked, 1(MRXHF1, OMIM #309580). These two diseases present similar clinical manifestations and the same pattern of inheritance.
We reported a 3-year-old boy with intellectual disability, language impairment, hypotonia, and mild craniofacial abnormalities (flat nasal bridge, small and triangular nose, anteverted nostrils, and widely spaced incisors) and reviewed MRXHF1 cases. At an early stage, the patient developed global developmental delay (GDD). After 6 months of rehabilitation therapy, the patient's motor ability did not make big progress, as well as his speech or nonverbal communication. We performed whole-genome sequencing (WGS), Sanger sequencing, reverse transcription-polymerase chain reaction (RT-PCR), and X-inactivation studies. A novel hemizygous intronic variant in (c.5786+4A>G; NM_000489.6) was identified, which led to exon 24 skipping. The carrier mother showed extremely skewed X-chromosome inactivation (XCI). These results may contribute to the patient's phenotypes.
The novel hemizygous intronic variant in is the genetic etiology of the boy. Identification of this variant is helpful for parents to take prenatal diagnostic tests. Also, this new case expands the phenotypes of MRXHF1 and the mutational spectrum of the gene.
α地中海贫血/智力障碍综合征（ATR-X）（OMIM编号#301040）最早由威尔基等人描述（1）。多项研究发现，患有血红蛋白H（Hb H）病显著一致临床表型和严重智力障碍的儿童携带（，OMIM300032）基因变异。随着外显子组测序（ES）的最新发展，无α地中海贫血的严重至重度智力障碍的基因变异与智力障碍-低张力面容综合征，X连锁，1（MRXHF1，OMIM编号#309580）有关。这两种疾病表现出相似的临床表现和相同的遗传模式。
我们报告了一名3岁男孩，患有智力障碍、语言障碍、低张力和轻度颅面异常（鼻梁扁平、鼻小且呈三角形、鼻孔前倾和门牙间距宽），并回顾了MRXHF1病例。早期，该患者出现全面发育迟缓（GDD）。经过6个月的康复治疗，患者的运动能力、言语或非言语交流均未取得显著进展。我们进行了全基因组测序（WGS）、桑格测序、逆转录聚合酶链反应（RT-PCR）和X染色体失活研究。在（c.5786+4A>G；NM_000489.6）中鉴定出一种新的半合子内含子变异，导致外显子24跳跃。携带该变异的母亲表现出极其偏斜的X染色体失活（XCI）。这些结果可能导致了患者的表型。
中的新半合子内含子变异是该男孩的遗传病因。鉴定该变异有助于父母进行产前诊断测试。此外，这个新病例扩展了MRXHF1的表型和基因的突变谱。
