Genotype-Phenotype Correlations in 2q37-Deletion Syndrome: An Update of the Clinical Spectrum and Literature Review

Abstract

2q37 microdeletion/deletion syndrome (2q37DS) is one of the most common subtelomeric deletion disorders, caused by a 2q37 deletion of variable size. The syndrome is characterized by a broad and diverse spectrum of clinical findings: characteristic facial dysmorphism, developmental delay/intellectual disability (ID), brachydactyly type E, short stature, obesity, hypotonia in infancy, and abnormal behavior with autism spectrum disorder. Although numerous cases have been described so far, the exact mapping of the genotype and phenotype have not yet been achieved.

Materials and methods: In this study we analyzed nine newly diagnosed cases with 2q37 deletion (3 male/6 female, aged between 2 and 30 years old), and followed up at the Iasi Regional Medical Genetics Centre. All patients were tested first with MLPA using combined kits P036/P070 subtelomeric screening mix and follow-up mix P264; after, the deletion size and location were confirmed via CGH-array. We compared our findings with the data of other cases reported in the literature.

Results: From nine cases, four had pure 2q37 deletions of variable sizes, and five presented deletion/duplication rearrangements (with chromosomes 2q, 9q, and 11p). In most cases, characteristic phenotypic aspects were observed: 9/9 facial dysmorphism, 8/9 global developmental delay and ID, 6/9 hypotonia, 5/9 behavior disorders, and 8/9 skeletal anomalies-especially brachydactyly type E. Two cases had obesity, one case had craniosynostosis, and four had heart defects. Other features found in our cases included translucent skin and telangiectasias (6/9), and a hump of fat on the upper thorax (5/9).

Conclusions: Our study enriches the literature data by describing new clinical features associated with 2q37 deletion, and possible genotype-phenotype correlations.

Keywords: 2q37 deletion; brachydactyly E; genotype–phenotype correlations; intellectual disability.

Figure 1

2q37 Deletion mapping that shows the size and location of the chromosomal 2q deletions found in our study. With blue, cases P1, P2, P3, and P4 are pure deletions; with orange, cases P5, P6, P7, P8, and P9 are deletions associated to other CNVs.

Figure 2

Partial images of MLPA results for follow-up probe mix P264 in bar chart format generated by Coffalyser.Net software showing the following: (A) Case 5—an approximately 1.7Mb (chr2:241,179,100–242,441,800-hg18) heterozygous deletion of the 2q37 subtelomeric region (ratio < 0.7), and duplication (3 copies, ratio > 1.3) in the continuation of the deleted part, possibly more extensive than the analyzed region of 3.3 Mb (chr2:237,961,400–240,609,300); (B) Case 9—heterozygous deletion of the 2q37 subtelomeric region (ratio < 0.7), possibly more extensive than the analyzed region of 5 Mb (chr2: 237,961,400–242,441,800-hg18).

Figure 3

Array-CGH results generated by Agilent CytoGenomics Software: with blue, duplication; with red, deletion. (A) Case 5—the 1.84 Mb deletion and the approximately 42.2 Mb duplication in 2q32-q37 region arr[GRCh38] q32.1-q37.3 (198008040_240171196)x3, arr[GRCh38] 2q37.3(240256938_242098125)x1 (the enlarged view of the rearrangement). (B) Case 9—the 5.02 Mb deletion in 2q37 region and the 1.05 Mb subtelomeric 11p15 duplication (enlarged view): arr[GRCh38] 2q37.3(237134728_242126245)x1, arr[GRCh38] 11p15.5(1676931_2732095)x3.

Figure 4

Dysmorphic face in following: (A) case P1 at 30 years old, (B) case P8 at 13 years old, (C) case P5 at 9 years old, (D) case P9 at 12 years old.

Figure 5

Hands and feet defects: (A) small puffy hands with brachydactyly type E in P1, (B) brachydactyly type E P2, (C) clinodactyly in P4, (D) small puffy feet, abnormal insertion of toes and brachydactyly type E in P1, (E) feet with brachydactyly type E—case 4, (F) asymmetric limbs in P8.