Background: Acid Sphingomyelinase Deficiency (ASMD), encompassing Niemann-Pick disease (NPD) types A and B, is a rare lysosomal storage disorder caused by pathogenic variants in the SMPD1 gene. In populations with high rates of consanguinity, the prevalence of such autosomal recessive disorders is significantly elevated, necessitating robust molecular diagnostic and preventive strategies to align with any national preventive strategies. Methods: In this study, we performed molecular analysis on 13 families with a history of ASMD. Genetic screening was conducted using Sanger sequencing of the SMPD1 gene on all 6 exons. Prenatal diagnosis (PND) was performed for some high-risk pregnancies via chorionic villus sampling (CVS). STR-based linkage analysis using STR markers flanking the SMPD1 gene was used to confirm autozygosity and segregation pattern, and in addition, during fetal sample analysis, to confirm mutation finding, sample authenticity, and exclude maternal cell contamination. Results: Molecular analysis led to the identification of various pathogenic variants, including missense, nonsense, frameshift mutations, and small deletions. The p. Arg498His variant emerged as a recurrent mutation, suggesting a potential founder effect in the studied population. Furthermore, two novel variants c.421 G>A (p.Glu141Asp), and c.850 C>T (p.His284Tyr) were identified, expanding the global mutational spectrum of SMPD1. Out of the pregnancies referred for PND, we successfully identified affected, carrier, and healthy fetuses, providing valuable information for reproductive decision-making. One case of compound heterozygosity was observed in a non-related couple, highlighting the genetic complexity even in consanguineous settings. Conclusion: Our findings identified 10 different mutations, indicating the diverse mutation spectrum of the SMPD1 gene in the Iranian population. We also identified two new mutations, adding extra information to the available data. Most mutations were found in families with early child death, highlighting the importance of prenatal diagnosis in our population. These results emphasize the necessity of carrier screening and early molecular intervention to reduce the disease burden in populations with high consanguinity.

Background: Acid Sphingomyelinase Deficiency (ASMD), encompassing Niemann-Pick disease (NPD) types A and B, is a rare lysosomal storage disorder caused by pathogenic variants in the SMPD1 gene. In populations with high rates of consanguinity, the prevalence of such autosomal recessive disorders is significantly elevated, necessitating robust molecular diagnostic and preventive strategies to align with any national preventive strategies. Methods: In this study, we performed molecular analysis on 13 families with a history of ASMD. Genetic screening was conducted using Sanger sequencing of the SMPD1 gene on all 6 exons. Prenatal diagnosis (PND) was performed for some high-risk pregnancies via chorionic villus sampling (CVS). STR-based linkage analysis using STR markers flanking the SMPD1 gene was used to confirm autozygosity and segregation pattern, and in addition, during fetal sample analysis, to confirm mutation finding, sample authenticity, and exclude maternal cell contamination. Results: Molecular analysis led to the identification of various pathogenic variants, including missense, nonsense, frameshift mutations, and small deletions. The p. Arg498His variant emerged as a recurrent mutation, suggesting a potential founder effect in the studied population. Furthermore, two novel variants c.421 G>A (p.Glu141Asp), and c.850 C>T (p.His284Tyr) were identified, expanding the global mutational spectrum of SMPD1. Out of the pregnancies referred for PND, we successfully identified affected, carrier, and healthy fetuses, providing valuable information for reproductive decision-making. One case of compound heterozygosity was observed in a non-related couple, highlighting the genetic complexity even in consanguineous settings. Conclusion: Our findings identified 10 different mutations, indicating the diverse mutation spectrum of the SMPD1 gene in the Iranian population. We also identified two new mutations, adding extra information to the available data. Most mutations were found in families with early child death, highlighting the importance of prenatal diagnosis in our population. These results emphasize the necessity of carrier screening and early molecular intervention to reduce the disease burden in populations with high consanguinity.