Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene

Abstract

<jats:title>Abstract</jats:title><jats:sec id="j_cclm-2020-0306_abs_001_w2aab3b7b1b1b6b1aab1c11b2Aa"><jats:title>Objectives</jats:title><jats:p>Gaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid β-glucosidase (<jats:italic>GBA</jats:italic>) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation.</jats:p></jats:sec><jats:sec id="j_cclm-2020-0306_abs_002_w2aab3b7b1b1b6b1aab1c11b3Aa"><jats:title>Methods</jats:title><jats:p>Descriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, β-glucocerebrosidase activity, variants pathogenic in <jats:italic>GBA</jats:italic> gene and biomarkers for monitoring treatment were collected from digital medical record.</jats:p></jats:sec><jats:sec id="j_cclm-2020-0306_abs_003_w2aab3b7b1b1b6b1aab1c11b4Aa"><jats:title>Results</jats:title><jats:p>Twenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T&gt;C (p.Tyr313His)] were identified in the <jats:italic>GBA</jats:italic> gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A&gt;G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T&gt;C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T&gt;C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A&gt;G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder.</jats:p></jats:sec><jats:sec id="j_cclm-2020-0306_abs_004_w2aab3b7b1b1b6b1aab1c11b5Aa"><jats:title>Conclusions</jats:title><jats:p>The c.1226A&gt;G (p.Asn409Ser) and c.1448T&gt;C (p.Leu483Pro) mutations were the most common. The c.937T&gt;C (p.Tyr313His) was identified as a novel mutation. The c.1448T&gt;C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A&gt;G (p.Asn409Ser) mutation has not been associated it.</jats:p></jats:sec>

Newborn screening for Gaucher disease in Japan

“…GBA analysis revealed that she was homozygous for the p.L483P (c.1448 T > C) variant. p.L483P is the most common pathogenic variant in Japanese patients with GD [ 22 ] and is involved in the development of neurological symptoms [ 23 , 24 ]. ERT was started at the age of 84 days and improved her anemia, thrombocytopenia, and hepatosplenomegaly.…”

“…This variant is the most frequent in patients with neuropathic GD [ 33 ] and Japanese patients with GD [ 22 ]. Although most patients with the homozygous p.L483P variant develop GD3 [ 24 , 30 ], they may have a variety of clinical courses [ 23 ]. There is an unclear relationship between the clinical course of GD and residual GCase activity [ 23 ].…”

Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1

“…Genetic testing can be done as a primary test for GD diagnosis. However, since many GBA1 variants are private, the chances of finding variants of uncertain significance (VUS) are quite high [25,[143][144][145][146][147][148][149][150][151][152][153][154][155]. In this case, confirmation of diagnosis through the assessment of enzymatic activity in patient's cells is mandatory.…”

“…While 4 pathogenetic variants (N370S; L444P, c.84-85 insG; IVS + 1G > A) account for 90% of alleles within Ashkenazi Jews, they account only for about 50-75% of alleles in non-Jewish populations. In addition, about 10% of patients present large deletions/ recombinant alleles [25,[143][144][145][146][147][148][149][150][151][152][153][154][155][157][158][159][160][161][162][163][164].…”

“…Long template specific PCR amplification of the GBA1 gene (and not the pseudogene) followed by Sanger sequencing allows the identification of single base pair variants and most recombinant alleles leading to molecular diagnosis of GD about 95-98% of cases [25,[143][144][145][146][147][148][149][150][151][152][153][154][155]; however, this method fails to detect large deletions [144,151,165,166].…”