Abstract
BackgroundWe 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.MethodsWe performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members.ResultsWe identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family.ConclusionsWe 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.
Highlights
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 identified a five-generation kindred with four successive generations affected by congenital neutropenia (10 individuals; eight had monocytosis – available blood counts in Table S1) and five generations affected by hearing loss of varying severity (13 individuals) (Fig. 1a, Table 1)
Sanger sequencing of GATA2 was performed due to partial overlap in the phenotypes observed within the family, but no pathogenic coding variants were found
Summary
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. 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. Severe congenital neutropenia (SCN) was first described by Kostmann in 1956 in 14 individuals from 9 consanguineous families [1]. It has been suggested that these variants impair neutrophil maturation via defective CSF3R signaling as the number of G-CSF receptors on myeloid precursors of SCN patients is elevated
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