Heterogeneity of disease‐causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants

Abstract

The aim was to determine disease‐causing variants in the GALT gene which codes for the enzyme galactose‐1‐phosphate uridylyltransferase. Loss of activity of this enzyme causes classical galactosemia—a life threatening, treatable disorder, included in the Swedish newborn screening program since 1967. A total of 66 patients with the disease are known in Sweden and 56 index patients were investigated. An additional two patients with Duarte galactosemia were included. The disease‐causing variants were identified in all patients. As reported from other countries only a few variants frequently recur in severe disease. The two variants p.(Gln188Arg) (c.563A>G) and p.(Met142Lys) (c.425T>A) are present in several index patients whereas the remaining are found in one to three patients each. The most common variant, p.(Gln188Arg), has an allele frequency of 51% in the cohort. A total of 16 novel variants were found among the 33 different variants in the cohort. Two of these are synonymous variants affecting splicing, demonstrating the importance of the evaluation of synonymous variants at the cDNA level. Concise sentence: Galactosemia is a rare disease in Sweden and the disease‐causing variants are heterogenous including two synonymous variants.

ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder

“…Pro163=) in ECHS1 provides some sort of advantage with respect to fitness to have become that enriched in this population. Synonymous variants have also been reported in other inborn metabolic diseases (Ohlsson et al, 2019;Salomons et al, 2007). They produce different levels of both, normal and aberrant transcripts from the same allele.…”

“…Although synonymous variants are rarely identified as disease causing there is now increasing evidence that the impact of silent mutations is vastly underappreciated. For example a recent study, investigating the mutational spectrum for galactosemia in Sweden, revealed two pathogenic silent variants (p.Pro36 = and p.Pro109=) in GALT, resulting in abnormal splicing leading to a decreased residual GALT activity and classic galactosemia phenotype (Ohlsson, Hunt, Wedell, & von Döbeln, 2019). A machine learning algorithm using a deep neural network process to more accurately predict splice junctions estimates that 10% of disease causing mutations are due to cryptic splice sites including synonymous variants (Jaganathan et al, 2019) (Strauss et al, 2015).…”

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

“…A less severe presentation of galactosemia is associated with the Duarte variant [ 138 ]. Recently, genome wide association studies conducted in Argentina [ 139 ] identified 14 different mutations among 72 unrelated alleles and similar studies conducted in Sweden [ 140 ], Greece [ 141 ], Korea [ 142 ], Turkey [ 143 ], Lithuania [ 144 ] and India [ 145 ] have reported mutations that are confined to specific regions and populations. Current approaches for the treatment of galactosemia include neonatal screening [ 146 ] followed by dietary management via the reduction or substitution of galactose and lactose; however, long-term therapy required additional interventions such as molecular chaperones to correct the misfolded [ 147 ] GALT enzyme [ 148 ] and the reliance on animal models to characterize the genetic association between GALT mutations and galactosemia [ 149 ].…”