Clinical delineation of 18q11‐q12 microdeletion: Intellectual disability, speech and behavioral disorders, and conotruncal heart defects

• Published in: Molecular genetics & genomic medicine Vol. 7; no. 9; pp. e896 - n/a
• Main Authors: Rojnueangnit, Kitiwan, Charalsawadi, Chariyawan, Thammachote, Weerin, Pradabmuksiri, Ariya, Tim‐Aroon, Thipwimol, Novelli, Antonio, Loddo, Sara, Briuglia, Silvana, Concetta, Cutrupi M., Wattanasirichaigoon, Duangrurdee, Jinawath, Natini
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2019; John Wiley and Sons Inc; Wiley
• Subjects: 18q11‐q12 microdeletion; Abdomen; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Age; Autism; Child, Preschool; chromosomal microarray; Chromosome 18; Chromosome Deletion; Chromosomes; Chromosomes, Human, Pair 18 - genetics; Congenital diseases; conotruncal heart defects; Correlation analysis; Databases, Genetic; Defects; Delay; Delineation; Female; GATA6; GATA6 Transcription Factor - genetics; Genes; Genotype & phenotype; Genotypes; Haploinsufficiency; Heart; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Infant; Intellectual disabilities; intellectual disability; Intellectual Disability - genetics; Intellectual Disability - pathology; Language Development Disorders - genetics; Language Development Disorders - pathology; Male; Medicine; Mental Disorders - genetics; Mental Disorders - pathology; Mutation; Original; Patients; Phenotypes; Puberty; Pulmonary arteries; Speech; GATA6; chromosomal microarray; 18q11-q12 microdeletion; conotruncal heart defects; autism; intellectual disability
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.896

Background Since the establishment of chromosomal microarrays in clinical practice, many new microdeletion/microduplication syndromes have been identified, including 18q11.2 microdeletion. Chromosome 18q deletion syndrome is commonly classified into distal deletion and a much rarer proximal interstitial deletion spanning the 18q11.2‐q21.1 region. Methods We report two new patients and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature, with more proximal 18q deletions involving 18q11‐q12 (band 1 only; 17.2–43.5 Mb position) deletion. Results Common presentations of 18q11‐q12 deletions include developmental delay/intellectual disability (DD/ID) (82%); speech delay/autism/attention deficit and hyperactivity/other behavioral problems (30%); conotruncal heart defects (15%); and subtle/non‐specific facial dysmorphism. The deletion in four out of five cases with cardiac defect was distal to GATA6, suggesting an alternative mechanism other than haploinsufficiency of GATA6 as an underlying cause of cardiac malformations. Precocious puberty with advanced skeletal age was first observed in one patient, suggesting a unique and expanded phenotype of proximal 18q deletion. When comparing genotype–phenotype correlations from the present study with previous reports, the critical regions for selected phenotypes of 18q11‐q12 deletion syndrome could be narrowed down as follows: 38.8–43.5 Mb for moderate to severe DD/ID, 19.6–24.4 Mb and 26.9–28.6 Mb for conotruncal heart defect. Conclusion The detailed clinical delineation of the proximal 18q deletions identified in this study should contribute to better understanding of the genotype–phenotype correlations and better long‐term care of patients with this rare syndrome. We report two new patients of proximal 18q11‐q12 microdeletion syndrome and review 27 additional cases in DECIPHER/ClinGen databases and four cases from the literature about these proximal deletions.