DataSheet1_Case Report: Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis.docx

Bone marrow failure represents an umbrella diagnosis for several life-threatening disorders. In many people, the etiology remains unknown for a long time, leading to an odyssey to diagnosis, with numerous tests performed and sometimes inappropriate treatment. Biallelic pathogenic variants in the DNAJC21 gene were recently discovered to cause bone marrow failure syndrome type 3, having phenotypic overlap with Fanconi anemia, dyskeratosis congenita, Shwachman–Diamond syndrome, and Diamond–Blackfan anemia. Herein, we report an 8-year-old boy, with normal intellect, presenting bone marrow failure; growth retardation; failure to thrive; recurrent infections (including sepsis); cryptorchidia; skeletal, skin, teeth, and hair abnormalities; joint hypermobility; eczema; palpebral ptosis; high myopia; rod–cone retinal dystrophy; and short telomeres. He underwent several tests and evaluations, including genetic investigations (panel and exome sequencing), before the DNAJC21 gene was known to cause disease. Whole-genome sequencing performed at the age of 7 years, identified two novel, pathogenic, and compound heterozygous variants in the DNAJC21 gene: NM_001012339.3:c.148C>T (stopgain-maternal origin), p.Gln50∗ and c.643_644delinsTTT (frameshift paternal origin), and p.Lys215Phefs∗71. He received aggressive treatments for his multisystem disease: blood cell transfusions, high-dose corticosteroids, immunoglobulins, multiple antibiotics, vitamins, growth hormone, and others. However, allogeneic hematopoietic stem cell transplantation was avoided. The clinical evolution of bone marrow failure and recurrent infections stabilized with age, yet the myopia progressed. Exocrine pancreatic insufficiency was not detected. This report widens the molecular and clinical understanding of bone marrow failure syndrome type 3. Genome sequencing directed a precise diagnosis that improved patient management and enabled family genetic counseling.

骨髓衰竭症是一个涵盖多种危及生命疾病的总称。在众多患者中，其病因长时间未知，导致诊断之旅漫长而曲折，期间需进行众多检测，有时甚至接受不恰当的治疗。近期研究发现，DNAJC21基因的双等位基因致病性变异可导致骨髓衰竭症第3型，其表型与范可尼贫血、先天性角化不良、舒瓦茨曼-戴米安综合征和迪安-布莱克范贫血存在重叠。在本研究中，我们报道了一名8岁男孩的病例，他智力正常，表现为骨髓衰竭、生长发育迟缓、生长迟滞、反复感染（包括败血症）、隐睾、骨骼、皮肤、牙齿和毛发异常、关节过度活动、湿疹、眼睑下垂、高度近视、视杆-视锥视网膜变性以及端粒缩短。在DNAJC21基因被确认为疾病病因之前，他经历了包括基因检测（基因芯片和全外显子测序）在内的多项检测和评估。在7岁时进行的全基因组测序发现，DNAJC21基因存在两个新的、致病性的、复合杂合变异：NM_001012339.3:c.148C>T（终止密码子获得性突变，母亲来源），p.Gln50∗和c.643_644delinsTTT（移码突变，父亲来源），p.Lys215Phefs∗71。他接受了针对其多系统疾病的大胆治疗：血液细胞输注、大剂量皮质类固醇、免疫球蛋白、多种抗生素、维生素、生长激素等。然而，他避免了同种异体造血干细胞移植。随着年纪的增长，骨髓衰竭和反复感染的临床进展得到了稳定，但近视却进一步恶化。未检测到外分泌胰腺功能不足。本报告扩展了我们对骨髓衰竭症第3型的分子和临床认识。基因组测序指导下的精确诊断改善了患者管理，并使家族遗传咨询成为可能。