Schindler disease is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in alpha-N-acetylgalactosaminidase (α-NAGA) activity due to defects in the NAGA gene. Accumulation of the enzyme’s substrates results in clinically heterogeneous symptoms ranging from asymptomatic individuals to individuals with severe neurological manifestations. Here, a 5-year-old Emirati male born to consanguineous parents presented with congenital microcephaly and severe neurological manifestations. Whole genome sequencing revealed a homozygous missense variant (c.838C>A; p.L280I) in the NAGA gene. The allele is a reported SNP in the ExAC database with a 0.0007497 allele frequency. The proband’s asymptomatic sister and cousin carry the same genotype in a homozygous state as revealed from the family screening. Due to the extreme intrafamilial heterogeneity of the disease as seen in previously reported cases, we performed further analyses to establish the pathogenicity of this variant. Both the proband and his sister showed abnormal urine oligosaccharide patterns, which is consistent with the diagnosis of Schindler disease. The α-NAGA activity was significantly reduced in the proband and his sister with 5.9% and 12.1% of the mean normal activity, respectively. Despite the activity loss, p.L280I α-NAGA processing and trafficking were not affected. However, protein molecular dynamic simulation analysis revealed that this amino acid substitution is likely to affect the enzyme’s natural dynamics and hinders its ability to bind to the active site. Functional analysis confirmed the pathogenicity of the identified missense variant and the diagnosis of Schindler disease. Extreme intrafamilial clinical heterogeneity of the disease necessitates further studies for proper genetic counseling and management.
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We are indebted to the family for their participation in this study.
This study was supported by research grants from the United Arab Emirates University (grants 31R018 and 31R134).
Ethics Approval and Consent to Participate
All procedures performed in studies involving human participants were in accordance with Al-Ain Medical Human Research Ethics Committee (AMHREC) according to the national regulations (approval numbers 10/09 and ERH-2015-3241 15–115) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Samples and images were collected from the proband and his sister after obtaining written informed consents from the parents.
Informed consent was obtained from all individual participants included in the study. Additional informed consents were obtained from all individual participants for whom identifying information is included in this article.
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Mohamed, F.E., Al Sorkhy, M., Ghattas, M.A. et al. A Novel Homozygous Missense Variant in the NAGA Gene with Extreme Intrafamilial Phenotypic Heterogeneity. J Mol Neurosci 70, 45–55 (2020). https://doi.org/10.1007/s12031-019-01398-6