Abstract

Introduction

Mutations in JAM2 have been linked to ~ 2% of primary familial brain calcification (PFBC) cases. PFBC is a rare neurological disorder characterized by excessive calcium deposition in the brain. It causes movement disorders and psychiatric problems. Six other genes were identified as causing PFBC. However, the genetic basis of ~ 50% of PFBC cases remains unknown. This study presented the results of a comprehensive analysis of five unrelated Iranian PFBC families.

Methods

Clinical and paraclinical features of all patients were recorded. Whole-exome sequencing (WES) was done on the DNAs of probands. Data was analyzed, and haplotypes were determined.

Results

WES identified two homozygous variants in JAM2 across four families: a novel variant, c.426dup:p.Ser143Leufs*23, in one family and a known mutation, c.685C > T:p.Arg229*, in the remaining three families. Haplotype analysis using six intragenic single-nucleotide polymorphisms (SNPs) in JAM2 revealed an identical haplotype in probands who carried the same mutation, whereas two other probands presented diverse haplotypes.

Conclusion

Based on our results, p.Arg229* may be a founder mutation in the Iranian population. The variant has been detected in two out of seven other reported JAM2-related families who may originate from the Middle East and exhibit an identical haplotype. Even though this particular mutation may not be classified as a founder mutation, it does appear to be a hotspot, given that it has been observed in 45% of the 11 JAM2-associated families. Our study expanded the clinical features and mutation spectrum of JAM2 and revealed that mutations in JAM2 may be more common than previously reported.

中文翻译：

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JAM2 变异在原发性家族性脑钙化 (PFBC) 病例中比出现的情况更为常见；可能是由于创始人突变

摘要

介绍

JAM2突变与约 2% 的原发性家族性脑钙化 (PFBC) 病例有关。PFBC 是一种罕见的神经系统疾病，其特征是大脑中钙沉积过多。它会导致运动障碍和精神问题。其他六个基因被确定为导致 PFBC 的原因。然而，约 50% 的 PFBC 病例的遗传基础仍不清楚。本研究提出了对五个不相关的伊朗 PFBC 家族进行综合分析的结果。

方法

记录所有患者的临床和临床旁特征。对先证者的 DNA 进行全外显子组测序 (WES)。分析数据并确定单倍型。

结果

WES 在四个家族中鉴定出JAM2中的两个纯合变异：一个家族中的一种新变异 c.426dup:p.Ser143Leufs*23，以及其余三个家族中的一种已知突变 c.685C > T:p.Arg229*。使用JAM2中的六个基因内单核苷酸多态性 (SNP) 进行的单倍型分析显示，携带相同突变的先证者具有相同的单倍型，而其他两个先证者则呈现出不同的单倍型。

结论

根据我们的结果，p.Arg229* 可能是伊朗人群中的一个创始人突变。在其他七个报道的JAM2相关家族中的两个中也检测到了该变异，这些家族可能来自中东并表现出相同的单倍型。尽管这种特殊突变可能不被归类为创始人突变，但它似乎确实是一个热点，因为它已在 11 个JAM2相关家族中的 45% 中观察到。我们的研究扩展了JAM2的临床特征和突变谱，并揭示JAM2的突变可能比之前报道的更常见。