表现为杂合性缺失并影响印记基因的表观基因组变异是儿童自闭症谱系障碍和智力残疾的一种分子机制。

[Epigenomic variations manifesting as a loss of heterozygosity affecting imprinted genes represent a molecular mechanism of autism spectrum disorders and intellectual disability in children].

作者信息

Iourov I Y, Vorsanova S G, Zelenova M A, Vasin K S, Kurinnaia O S, Korostelev S A, Yurov Yu B

机构信息

Mental Health Research Center, Moscow, Russia; Veltishchev Research Clinical Institute of Pediatric of Pirogov Russian National Research Medical University, Moscow, Russia; Russian Medical Academy for Postgraduate Continuing Education, Moscow, Russia.

Mental Health Research Center, Moscow, Russia; Veltishchev Research Clinical Institute of Pediatric of Pirogov Russian National Research Medical University, Moscow, Russia.

出版信息

Zh Nevrol Psikhiatr Im S S Korsakova. 2019;119(5):91-97. doi: 10.17116/jnevro201911905191.

DOI:10.17116/jnevro201911905191

PMID:31317896

Abstract

AIM

Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy.

MATERIAL AND METHODS

Five hundred and four patients with autism spectrum disorders and intellectual disability were examined.

RESULTS

LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci.

CONCLUSION

The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.

摘要

目的

在使用分子核型分析（单核苷酸多态性阵列）的研究中经常检测到长片段纯合性（LCSH）。尽管这类变异能够提供有关父母亲属关系、单亲二体性和染色体重排的有意义数据，但LCSH很少被视为神经发育障碍可能的表观遗传原因。尽管它们与印记直接相关，但印记基因座中的LCSH尚未从致病性方面进行考虑。本研究旨在研究包含先前与特发性智力障碍、自闭症、先天性畸形和/或癫痫儿童疾病相关的印记基因的染色体区域中的LCSH。

材料与方法

对504例自闭症谱系障碍和智力障碍患者进行了检查。

结果

在40例（7.9%）个体中鉴定出影响与各种疾病相关的印记基因座的LCSH。23例患者的染色体区域7q21.3受到影响，12例为15q11.2，5例为11p15.5，4例为7q32.2。4例患者有2个影响印记基因座的LCSH。除了7q31.3 - 3q32.3（约4 Mbp）区域的一个LCSH外，所有LCSH均为1 - 1.6 Mbp。临床上，这些病例类似于相应的印记疾病（如Silver-Russell、Beckwith-Wiedemann、Prader-Willi、Angelman综合征）。在8例（1.59%）病例中确定了父母亲属关系，这些病例在印记基因座未受LCSH影响。

结论

本研究表明，影响染色体区域7q21.3、7q32.2、11p15.5和15p11.2的LCSH出现在约7.9%的智力障碍、自闭症、先天性畸形和/或癫痫儿童中。因此，这类表观遗传突变在一组神经发育障碍儿童中显然很常见。小于2.5 - 10 Mbp的LCSH在分子核型分析（单核苷酸多态性阵列）研究中通常被忽略，因此，智力障碍、自闭症或癫痫的一个重要表观遗传原因很可能仍未受到关注。