Literature review on genotype–phenotype correlation in patients with hereditary spherocytosis

Abstract

Hereditary spherocytosis (HS) is a prevalent inherited hemolytic disorder primarily reported in Caucasians. Recently, next‐generation sequencing (NGS) techniques have shown tremendous potential in the diagnosis of HS. HS commonly originates from variants in ANK1, SPTB, SLC4A1, SPTA1, and EPB42. This review is focused on 13 previous clinical studies on genotype–phenotype correlation, which might promote the role of causative variants in the diagnosis and prognosis of HS. Most studies have focused on the pediatric population and Asian countries. The occurrence of novel variants was common in each cohort, and variants with a high frequency of causative genes were demonstrated. In conclusion, patients with variants in SPTA1 and SLC4A1 were reported to have more severe and milder anemia, respectively. ANK1 and SPTB are the most common variants in patients with HS, and no significant difference in phenotypes was observed between patients with variants in ANK1 versus SPTB. The types and locations of variants might influence the phenotype of each genotype, whereas the roles of concomitant pathogenic genes and the source of variants deserve further investigation.

What is making this newborn excessively sleepy?

“…3 This leads to defects in multiple proteins, such as is seen in patients with both spectrin and ankyrin deficiencies. 3 Although most of these variants act in an autosomal dominant manner, autosomal recessive and de novo mutations also have been reported. 4 These variants result in a loss of the RBC membrane, which in turn reduces the cell's surface area to volume ratio, causing cells to become progressively more spherical in shape.…”

“…Variants in certain genes responsible for encoding the proteins of the membrane lead to this heterogenous group of disorders. The proteins affected—spectrin, ankyrin, band 3, and band 4.2—are each coded by different genes, but patients with hereditary spherocytosis may have variants in more than one gene 3. This leads to defects in multiple proteins, such as is seen in patients with both spectrin and ankyrin deficiencies 3.…”

“…The proteins affected—spectrin, ankyrin, band 3, and band 4.2—are each coded by different genes, but patients with hereditary spherocytosis may have variants in more than one gene 3. This leads to defects in multiple proteins, such as is seen in patients with both spectrin and ankyrin deficiencies 3. Although most of these variants act in an autosomal dominant manner, autosomal recessive and de novo mutations also have been reported 4.…”

“…A complete blood cell count with manual differential revealed a red blood cell (RBC) count of 1.87 million cells/mm3 (normal range, 3.8 to 5.6 million cells/mm3), hemoglobin of 6.2 g/dL (normal range, 10.7 to 17.3 g/dL), hematocrit of 16% (normal range, 33% to 51%), mean corpuscular hemoglobin concentration of 38.8 g/dL (normal range, 30 to 35 g/dL), and red cell distribution width of 20.6% (normal range, 11.5% to 14.5%). All other values were unremarkable.…”

A single‐center cohort study of patients with hereditary spherocytosis in Central Europe reveals a high frequency of novel disease‐causing genotypes

“…Genotype–phenotype correlations have corroborated that patients who carry heterozygous variants in ANK1 and SPTB (more often high‐impact) are phenotypically similar, and patients with heterozygous SLC4A1 variants (more often missense) have milder hematological phenotypes, 4,5,14 with considerable phenotypical variability in the different genetic subcohorts.…”