Amin Asmaa K, Krause Jeremias, Eggermann Thomas
Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Institute for Human Genetics and Genome Medicine, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
Mol Cytogenet. 2024 Mar 14;17(1):5. doi: 10.1186/s13039-024-00672-6.
Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging.
A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome.
The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.
Silver-Russel综合征（SRS）是一种先天性疾病，主要特征为宫内和出生后生长发育迟缓、相对头大以及特征性（面部）畸形。大多数患者表现为11p15印记中心区域1（IC1）低甲基化和7号染色体母源单亲二倍体（upd(7)mat），但此外，该队列中还报告了广泛的拷贝数变异（CNV）和单基因变异（SNV）。这些异质性发现反映了SRS与其他先天性疾病的临床重叠，但一些CNV是反复出现的，因此被认为是SRS相关位点。然而，这种分子异质性使得对具有SRS特征的患者进行诊断性检查的决策具有挑战性。
一名具有SRS临床特征但IC1低甲基化和upd(7)mat检测为阴性的女孩通过全基因组测序进行分析，以便在同一次检测中同时检测CNV和SNV。我们鉴定出一个11p13微重复，影响的区域与先前发表的具有Silver-Russel综合征临床特征的患者中报道的一个变异重叠。
在一名具有SRS特征的患者中鉴定出11p13微重复，证实了CNV对SRS相关表型的重要贡献，并加强了将11p13微重复综合征作为SRS鉴别诊断的证据。此外，我们可以确认全基因组测序是SRS及相关疾病患者的一种有价值的诊断工具，因为它可以在同一次检测中检测CNV和SNV，从而避免耗时的诊断检测过程。
