Two monogenic disorders masquerading as one: severe congenital neutropenia with monocytosis and non-syndromic sensorineural hearing loss

• Published in: BMC medical genetics Vol. 21; no. 1; p. 35
• Main Authors: Venugopal, Parvathy, Gagliardi, Lucia, Forsyth, Cecily, Feng, Jinghua, Phillips, Kerry, Babic, Milena, Poplawski, Nicola K, Rienhoff, Jr, Hugh Young, Schreiber, Andreas W, Hahn, Christopher N, Brown, Anna L, Scott, Hamish S
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.02.2020; BioMed Central; BMC
• Subjects: Accounting departments; Adult; Aged; Congenital Bone Marrow Failure Syndromes - complications; Congenital Bone Marrow Failure Syndromes - diagnosis; Congenital Bone Marrow Failure Syndromes - genetics; Congenital Bone Marrow Failure Syndromes - physiopathology; Congenital neutropenia; DNA sequencing; DNA-Binding Proteins - genetics; Exome - genetics; Family; Female; Genes; Genetic Diseases, Inborn - complications; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - genetics; Genetic Diseases, Inborn - physiopathology; Genetic disorders; Genetic screening; Genomics; Genotype & phenotype; Granulocytes; Hearing loss; Hearing Loss, Sensorineural - complications; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Hearing protection; Humans; Leukemia; Leukemia predisposition; Male; Middle Aged; Monocytosis; Mutation; Mutation - genetics; Myosin Heavy Chains - genetics; Neutropenia; Neutropenia - complications; Neutropenia - congenital; Neutropenia - diagnosis; Neutropenia - genetics; Neutropenia - physiopathology; Neutrophils; Pedigree; Phenotype; Phenotypes; Physiological aspects; Polygenic inheritance; Proteins; Retirement benefits; Transcription Factors - genetics; Whole Exome Sequencing; Australia; Congenital neutropenia; Polygenic inheritance; Hearing loss; Leukemia predisposition; Neutropenia
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-020-0971-z

We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.