Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

Naomi Baba; Anna Lengyel; Eva Pinti; Elzem Yapici; Isolde Schreyer; Thomas Liehr; György Fekete; Thomas Eggermann

doi:10.1186/s13039-022-00596-z

Microdeletions in 1q21 and 8q12.1 depict two additional molecular subgroups of Silver-Russell syndrome like phenotypes

Mol Cytogenet. 2022 May 13;15(1):19. doi: 10.1186/s13039-022-00596-z.

Authors

Naomi Baba^{1

2}, Anna Lengyel³, Eva Pinti³, Elzem Yapici⁴, Isolde Schreyer^{1

2}, Thomas Liehr¹, György Fekete³, Thomas Eggermann⁵

Affiliations

¹ Institute of Human Genetics, University of Jena, Jena, Germany.
² Praxis Für Humangenetik, Zentrum Für Ambulante Medizin, Jena, Germany.
³ 2Nd Department of Pediatrics, Semmelweis University Budapest, Budapest, Hungary.
⁴ Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
⁵ Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. teggermann@ukaachen.de.

Abstract

Background: Silver-Russell syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction, relative macrocephaly at birth, body asymmetry and typical facial features. Clinical and molecular heterogeneity is described in SRS. Common causes are loss of methylation of the imprinting center 1 in 11p15 and maternal uniparental disomy of chromosome 7. Other genetic alterations include disturbances of imprinted regions in 14q32, 7q32 and 11p15 as well as submicroscopic deletions and duplications. Single nucleotide variants in genes like IGF2, HMGA2, PLAG1, CDKN1C have also been identified in patients with SRS phenotypes. However, routine molecular diagnostics usually focus on 11p15 and chromosome 7, while less frequent causes are not systematically addressed.

Results: Here we report two patients with SRS features in which molecular karyotyping revealed microdeletions in 1q21 and 8q12.1 respectively. In a 3.5-year-old girl with postnatal growth restriction, feeding difficulties, relative macrocephaly and distinct SRS features a 2 Mb deletion in 1q21.1q21.2 was identified. Our second case is a 1.5-year-old boy with intrauterine and postnatal growth restriction, feeding difficulties and distinct facial features with a 77 kb deletion in 8q12.1 affecting PLAG1 as the only protein-encoding gene with known function.

Conclusions: The 1q21 region has not yet been assigned as an SRS region, although six patients with the same deletion and SRS features including relative macrocephaly have been described before. This new case adds to the evidence that distal 1q21 should be annotated as an SRS candidate region. The PLAGL1 alteration is the smallest deletion in 8q12.1 ever reported in a patient with SRS phenotype and it finally confirms that PLAG1 is the SRS causing gene in 8q12.1. To increase the diagnostic yield in patients with suspected SRS, we recommend both molecular karyotyping and next generation sequencing-based approaches.

Keywords: 1q21.q21.2 deletion; Molecular karyotyping; PLAG1; Silver-Russell syndrome (SRS).