Mucopolysaccharidosis Type VII (MPS VII): A locus-specific database of GUSB gene variants, genotypes and phenotypes
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Mucopolysaccharidosis type VII (MPS VII) is an ultrarare, autosomal recessive, lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Patients present variably with fetal effusions, skeletal dysplasia, dysmorphology, short stature, and cardio-pulmonary signs. MPS VII is diagnosed clinically in association with GUS enzyme deficiency and/or in association with two disease-associated variants in the GUSB gene. However, diagnosis can be confounded by the rarity of the disorder, variable presentation, and high frequency of variants of uncertain significance (VUS). A locus-specific database was established to collect and disseminate information about disease-associated variants in GUSB.
Methods:
We tabulated data from multiple clinical laboratories, ClinVar, and a consolidated, literature search to develop a comprehensive landscape of variants in the GUSB gene. Variants were annotated with patient demographic and phenotype data from public literature, including clinical and biochemical manifestations, and fetal effusion/NIHF history.
Results:
Conclusion:
This database reports 67% VUS among 329 GUSB variants. The high frequency of VUS in patients with two GUSB variants underscores the importance of parallel biochemical and molecular diagnosis of MPS VII. With the increasing use of genome-based newborn sequencing, timely reporting and classification of MPS VII disease-associated variants is necessary to support accurate diagnosis and enable clinical study of in utero fetal therapy for this disorder. Rapid reporting of novel and previously observed GUSB variants to public databases, including www.rarediseasegenes.com, ClinVar and LOVD, aids a better understanding of MPS VII and supports timely diagnosis.
Mucopolysaccharidosis type VII (MPS VII) is an ultrarare, autosomal recessive, lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Patients present variably with fetal effusions, skeletal dysplasia, dysmorphology, short stature, and cardio-pulmonary signs. MPS VII is diagnosed clinically in association with GUS enzyme deficiency and/or in association with two disease-associated variants in the GUSB gene. However, diagnosis can be confounded by the rarity of the disorder, variable presentation, and high frequency of variants of uncertain significance (VUS). A locus-specific database was established to collect and disseminate information about disease-associated variants in GUSB.
Methods:
We tabulated data from multiple clinical laboratories, ClinVar, and a consolidated, literature search to develop a comprehensive landscape of variants in the GUSB gene. Variants were annotated with patient demographic and phenotype data from public literature, including clinical and biochemical manifestations, and fetal effusion/NIHF history.
Results:
As of 17 May 2023, the database reports 329 unique variants among 235 individuals with ≥1 GUSB variant; 231 (70%) missense, 23 (7%) nonsense, 21 (7%) splicing, 17 (5%) frameshift, 11 (3%) silent, 9 (3%) UTR, 4 (1%) intronic, and 1 (<1%) complex rearrangement. Clinical classifications available for 316 variants were 66 (20%) Pathogenic, 39 (12%) Likely Pathogenic, 210 (67%) VUS, and 1 with conflicting interpretations.
Ninety patients (38%) received a positive molecular diagnosis for MPS VII (≥2P/LP GUSB variants) and 44 (19%) had a potential positive molecular diagnosis (≥2 variants with ≥1 VUS). Among these patients, 67 unique genotypes were observed (134 recurring genotypes) for which 46 (34%) genotypes occurred in only one patient. Additionally, 94 (40%) individuals had a single P/LP/VUS identified (variants mostly identified through a large gene panel, and other genetic findings are not included in this abstract). Clinical phenotypes were recorded for 106 patients with positive or potential positive findings. NIHF was the most common phenotype recorded for patients with a positive finding (n =65) and for those with a potential finding (n=24).
The GUSB LSDB is available at www.rarediseasegenes.com. This interactive, searchable website includes a variant table annotated with associated frequency, classification, impact, and publications. Data are provided in aggregate to protect patient privacy in this ultrarare disease.
Conclusion:
This database reports 67% VUS among 329 GUSB variants. The high frequency of VUS in patients with two GUSB variants underscores the importance of parallel biochemical and molecular diagnosis of MPS VII. With the increasing use of genome-based newborn sequencing, timely reporting and classification of MPS VII disease-associated variants is necessary to support accurate diagnosis and enable clinical study of in utero fetal therapy for this disorder. Rapid reporting of novel and previously observed GUSB variants to public databases, including www.rarediseasegenes.com, ClinVar and LOVD, aids a better understanding of MPS VII and supports timely diagnosis.