Consequences of chromsome18q deletions

Abstract

Providing clinically relevant prognoses and treatment information for people with a chromsome18q deletion is particularly challenging because every unrelated person has a unique region of hemizygosity. The hemizygous region can involve almost any region of 18q including between 1 and 101 genes (30 Mb of DNA). Most individuals have terminal deletions, but in our cohort of over 350 individuals 23% have interstitial deletions. Because of this heterogeneity, we take a gene by gene approach to understanding the clinical consequences. There are 196 genes on 18q. We classified 133 of them as dosage insensitive, 15 (8%) as dosage sensitive leading to haploinsufficiency while another 10 (5%) have effects that are conditionally haploinsufficient and are dependent on another factor, genetic or environmental in order to cause an abnormal phenotype. Thirty-seven genes (19%) have insufficient information to classify their dosage effect. Phenotypes attributed to single genes include: congenital heart disease, minor bone morphology changes, central nervous system dysmyelination, expressive speech delay, vesicouretreral reflux, polyposis, Pitt-Hopkins syndrome, intellectual disability, executive function impairment, male infertility, aural atresia, and high frequency sensorineural hearing loss. Additionally, identified critical regions for other phenotypes include: adolescent idiopathic scoliosis and pectus excavatum, Virchow-Robin perivascular spaces, small corpus callosum, strabismus, atopic disorders, mood disorder, IgA deficiency, nystagmus, congenital heart disease, kidney malformation, vertical talus, CNS dysmyelination growth hormone deficiency and cleft palate. Together these findings make it increasingly feasible to compile an individualized syndrome description based on each person's individuated genotype. Future work will focus on understanding molecular mechanisms leading to treatment.

Rheumatoid arthritis in an adult patient with mosaic distal 18q-, 18p- and dicentric ring chromosome 18

“…On the long arm, Merriman et al proposed a locus at 18q12-21 that influences development of autoimmune diseases 17 . Another gene of interest is NFATc1 (nuclear factor of activated T cells) at 18q23, implicated in maintaining the programmed death receptor (PD-1) and ligand (PD-L) pathway that is essential for regulatory T cells to terminate immune responses and protect against autoimmunity 18, 19 . It is difficult to establish a definitive genotype-phenotype association, but it appears plausible that this proposed autoimmune critical region and PTPN2 on the short arm, as well as NFATc1 on the long arm may play a part in the autoimmune diseases seen in our patient.…”

The Chromosome 18 Clinical Resource Center

“…The data used to create these Management Guides are from the participants at the Chromosome 18 Clinical Research Center and are based on in‐person assessments, medical and educational record review, and developmental survey data from 116 people with 18p‐, 343 people with 18q‐, 39 with Ring 18, and 70 with Tetrasomy 18p (Carter et al., ; Cody et al., ; Hasi‐Zogaj et al., ; O'Donnell et al., ). They reflect more than a quarter century of experience with affected individuals, many of whom we have followed since infancy.…”

B‐precursor acute lymphoblastic leukemia complicating 18q deletion syndrome

“…The 18q deletion syndrome, first described in 1964, is estimated to occur in one in 40,000 newborns . A cohort of more than 350 affected individuals was described in 2015 . This syndrome includes aural stenosis/atresia, hypotonia, developmental delay, and variable intellectual disability.…”

“…Deletions of chromosome 18q were among the first recognized congenital deletions . There are 196 genes on 18q and deletion sizes vary tremendously among different patients.…”

“…There are 196 genes on 18q and deletion sizes vary tremendously among different patients. Cody et al have determined that 15+ genes on 18q are dosage sensitive and thus haploinsufficient, whereas another 10+ genes are conditionally haploinsufficient . While none of these genes is a recognized tumor suppressor, there are genes whose function is poorly understood and whose insufficiency might contribute to the development of leukemia.…”