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

Parvathy Venugopal; Lucia Gagliardi; Cecily Forsyth; Jinghua Feng; Kerry Phillips; Milena Babic; Nicola K Poplawski; Hugh Young Rienhoff Jr; Andreas W Schreiber; Christopher N Hahn; Anna L Brown; Hamish S Scott

doi:10.1186/s12881-020-0971-z

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

BMC Med Genet. 2020 Feb 17;21(1):35. doi: 10.1186/s12881-020-0971-z.

Authors

Parvathy Venugopal^{1

2}, Lucia Gagliardi^{1

2

3

4

5}, Cecily Forsyth⁶, Jinghua Feng^{7

8}, Kerry Phillips⁹, Milena Babic^{1

2}, Nicola K Poplawski⁹, Hugh Young Rienhoff Jr¹⁰, Andreas W Schreiber^{2

7

8

11}, Christopher N Hahn^{1

2

3

8}, Anna L Brown^{1

2

8}, Hamish S Scott^{12

13

14

15

16}

Affiliations

¹ Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia.
² Centre for Cancer Biology, an alliance between SA Pathology and the University of South Australia, Adelaide, Australia.
³ School of Medicine, University of Adelaide, Adelaide, Australia.
⁴ Endocrine and Diabetes Unit, The Queen Elizabeth Hospital, Woodville South, Australia.
⁵ Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
⁶ Jarrett Street Specialist Centre, Gosford, Australia.
⁷ Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia, 5000, Australia.
⁸ School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Australia.
⁹ Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia.
¹⁰ Imago BioSciences, Inc., San Francisco, California, USA.
¹¹ School of Biological Sciences, University of Adelaide, Adelaide, Australia.
¹² Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia. hamish.scott@sa.gov.au.
¹³ Centre for Cancer Biology, an alliance between SA Pathology and the University of South Australia, Adelaide, Australia. hamish.scott@sa.gov.au.
¹⁴ School of Medicine, University of Adelaide, Adelaide, Australia. hamish.scott@sa.gov.au.
¹⁵ Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, PO Box 14, Rundle Mall, Adelaide, South Australia, 5000, Australia. hamish.scott@sa.gov.au.
¹⁶ School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, Australia. hamish.scott@sa.gov.au.

Abstract

Background: 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.

Methods: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members.

Results: 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.

Conclusions: 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.

Keywords: Congenital neutropenia; Hearing loss; Leukemia predisposition; Neutropenia; Polygenic inheritance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
DNA-Binding Proteins / genetics*
Exome / genetics
Exome Sequencing
Female
Genetic Diseases, Inborn / complications
Genetic Diseases, Inborn / diagnosis
Genetic Diseases, Inborn / genetics
Genetic Diseases, Inborn / physiopathology
Hearing Loss, Sensorineural / complications
Hearing Loss, Sensorineural / diagnosis
Hearing Loss, Sensorineural / genetics*
Hearing Loss, Sensorineural / pathology
Humans
Male
Middle Aged
Mutation / genetics
Myosin Heavy Chains / genetics*
Neutropenia / complications
Neutropenia / congenital*
Neutropenia / diagnosis
Neutropenia / genetics
Neutropenia / physiopathology
Pedigree
Phenotype
Transcription Factors / genetics*

Substances

DNA-Binding Proteins
GFI1 protein, human
Transcription Factors
myosin VI
Myosin Heavy Chains

Supplementary concepts

Neutropenia, Severe Congenital, Autosomal Recessive 3