The presence of two rare genomic syndromes, 1q21 deletion and Xq28 duplication, segregating independently in a family with intellectual disability.

Kyungsoo Ha,Tyler Graves,Cheol-Hee Kim,Yiping Shen,Hyung-Goo Kim

doi:10.1186/s13039-016-0286-0

Abstract

Background1q21 microdeletion syndrome is a rare contiguous gene deletion disorder with de novo or autosomal dominant inheritance patterns and its phenotypic features include intellectual disability, distinctive facial dysmorphism, microcephaly, cardiac abnormalities, and cataracts. MECP2 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by intellectual disability, global developmental delay, and other neurological complications including late-onset seizures. Previously, these two different genetic syndromes have not been reported segregating independently in a same family.Case presentationHere we describe two siblings carrying either a chromosome 1q21 microdeletion or a chromosome Xq28 duplication. Using a comparative genomic hybridization (CGH) array, we identified a 1.24 Mb heterozygous deletion at 1q21 resulting in the loss of 9 genes in a girl with learning disability, hypothyroidism, short stature, sensory integration disorder, and soft dysmorphic features including cupped ears and a unilateral ear pit. We also characterized a 508 kb Xq28 duplication encompassing MECP2 in her younger brother with hypotonia, poor speech, cognitive and motor impairment. The parental CGH and quantitative PCR (qPCR) analyses revealed that the 1q21 deletion in the elder sister is de novo, but the Xq28 duplication in the younger brother was originally inherited from the maternal grandmother through the mother, both of whom are asymptomatic carriers. RT-qPCR assays revealed that the affected brother has almost double the amount of MECP2 mRNA expression compared to other family members of both genders including maternal grandmother and mother who have the same Xq28 duplication with no phenotype. This suggests the X chromosome with an Xq28 duplication in the carrier females is preferentially silenced.ConclusionFrom our understanding, this would be the first report showing the independent segregation of two genetically unrelated syndromes, 1q21 microdeletion and Xq28 duplication, in a same family, especially in siblings. Although these two chromosomal abnormalities share some similar phenotypes such as intellectual disability, mild dysmorphic features, and cardiac abnormalities, the presence of two unrelated and rare syndromes in siblings is very unusual. Therefore, further comprehensive investigations in similar cases are required for future studies.

Highlights

The 1q21 microdeletion (MIM 612474) is a very rare genetic disorder with the deleted region spanning from 145.4 Mb to 147.8 Mb on chromosome 1. 1q21 microdeletion can occur de novo, but the majority of microdeletions are inherited from either parent in an autosomal dominant manner [1,2,3]
Microarray analysis revealed that the sister, our proband 1, carries 1.24-Mb heterozygous deletion at 1q21.1-1q21.2 region involving 9 genes (Fig. 3a, Table 2) and a 68 Kb deletion within intron 2 of Autism susceptibility candidate 2 (AUTS2) gene at 7q11.22 (Fig. 2b). 1q21 microdeletion is a contiguous gene deletion syndrome caused by the recurrent distal 1.35-Mb heterozygous deletion in the 1q21 region and characterized by dysmorphic facial features, mild-moderate developmental delay, intellectual disability, microcephaly and short stature [1, 2, 4]
The Reverse transcription-quantitative polymerase chain reaction (RT-quantitative PCR (qPCR)) analysis of methyl CpGbinding protein 2 (MECP2) expression levels revealed that proband 2 has almost double amount of MECP2 mRNA expression compared to other family members including maternal grandmother and mother who have the same MECP2 duplication, further suggesting that the skewed inactivation of X chromosome with MECP2 duplication in two female carriers

Summary

Introduction

The 1q21 microdeletion (MIM 612474) is a very rare genetic disorder with the deleted region spanning from 145.4 Mb to 147.8 Mb (hg19) on chromosome 1. 1q21 microdeletion can occur de novo, but the majority of microdeletions are inherited from either parent in an autosomal dominant manner [1,2,3]. The phenotypic features prompting diagnosis of 1q21 microdeletion include mild to moderate intellectual disability, learning disability, microcephaly, mildly dysmorphic facial features and skeletal malformations [1,2,3,4], cataracts [2, 5] and heart abnormalities [5, 6]. Because these clinical features are seen in other genetic disorders, 1q21 microdeletion is difficult to be diagnosed clinically and more often molecularly diagnosed by chromosomal microarray analysis [1, 2, 4]

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Discussion

Conclusion