Next-Generation Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Combined Features of Spherocytosis and Antley-Bixler Syndrome With Genital Anomalies and Disordered Steroidogenesis.

Fuying Song,Mu Du,Shunqiao Feng,Hui Yin,Xiaobo Chen,Xiang Shen,Rong Liu

doi:10.3389/fgene.2020.00976

Abstract

Conventionally, patients with combined rare diseases are often difficult to diagnose. This is because some clinicians tend to consider the multiple disease symptoms as the presentation of a complicated “syndrome.” This pattern of thinking also confines their way of filtering pathogenic mutations. Some real pathogenic mutations might be ignored due to not covering all disease presentations. Here we report the case of a girl who was suffering from spherocytosis and Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis. She remained undiagnosed even after targeted gene detection before. However, after performing next-generation sequencing and analyzing the sequencing data, we identified two mutations: c.2978T > A in ANK1 and c.1370G > A in POR. Our findings and experiences in diagnosing these mutations could contribute to the existing knowledge on the clinical and genetic diagnosis of patients with disease presentations in multiple systems.

Highlights

Hereditary spherocytosis (OMIM 182900), with a prevalence of 1/2,000, is a hemolytic disorder characterized by the presence of spherical erythrocytes on a peripheral blood smear (Gallagher, 2005; Perrotta et al, 2008; Yocum et al, 2012)
A heterozygous mutation (c.2978T > A) in ANK1 (NM_000037) and a homozygous mutation (c.1370G > A) in P450 oxidoreductase (POR) (NM_000941) were identified by next-generation sequencing (Supplementary Figure S1), which resulted in amino acid alterations p.I993N and p.R457H, respectively
Deficiency in any of these proteins may result in the disassociation of the erythrocyte membrane structure and subsequently reduce the surface-to-volume ratio, which causes hereditary spherocytosis (Eber and Lux, 2004)

Summary

Introduction

Hereditary spherocytosis (OMIM 182900), with a prevalence of 1/2,000, is a hemolytic disorder characterized by the presence of spherical erythrocytes on a peripheral blood smear (Gallagher, 2005; Perrotta et al, 2008; Yocum et al, 2012). Genes related to hereditary spherocytosis include ANK1, SLC4A1, SPTB, EPB42, and SPTA. Spherocytosis and Antley-Bixler Syndrome human erythroid ankyrin containing 1,880 amino acids. It combines tetramers of spectrin with the cytoplasmic domain of band three to form a spectrin-actin based membrane skeleton. This skeleton further interacts with the plasma membrane to stabilize the erythrocyte membrane (Gallagher, 2005). Defects in ankyrin synthesis or structure might result in instability of the erythrocyte membrane, causing hereditary spherocytosis

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Results

Conclusion