AUTHOR=Chirita-Emandi Adela , Petrescu Carmen-Angela-Maria , Zimbru Cristian G. , Stoica Florina , Marian Catalin , Ciubotaru Andreea , Bataneant Mihaela , Puiu Maria 

TITLE=Case Report: Novel Biallelic Variants in DNAJC21 Causing an Inherited Bone Marrow Failure Spectrum Phenotype: An Odyssey to Diagnosis

JOURNAL=Frontiers in Genetics

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.870233

DOI=10.3389/fgene.2022.870233

ISSN=1664-8021

ABSTRACT=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 years 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, rode-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 age 7 years, identified two novel, pathogenic, compound heterozygous variants, in DNAJC21 gene: NM_001012339.3:c.148C>T (stopgain-maternal origin), p.Gln50* and c.643_644delinsTTT (frameshift-paternal origin), p.Lys215Phefs*71. He received aggressive treatments for his multisystem disease: blood cell transfusions, high-dose corticosteroids, immunoglobulins, multiple antibiotics, vitamins, growth hormone and other. 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.