Defining the Critical Region for Intellectual Disability and Brain Malformations in 6q27 Microdeletions

Abstract

Terminal microdeletions of the long arm of chromosome 6 are associated with a phenotype that includes multiple brain malformations, intellectual disability, and epilepsy. A 1.7-Mb region has been proposed to contain a gene responsible for the brain anomalies. Here, we present the case of a 12-year-old girl with multiple brain alterations and moderate intellectual disability with a 18-kb deletion in chromosome 6q27, which is smaller than the microdeletions previously described by microarray analysis. We refined the smallest region of overlap possibly associated with the phenotype of brain malformations and intellectual disability to a segment of 325 kb, comprising the <i>DLL1</i>,<i> PSMB1</i>,<i> TBP</i>, and<i> PDCD2 </i>genes since these genes were structurally and/or functionally lost in the smaller deletions described to date. We hypothesize that <i>DLL1</i> is responsible for brain malformations and possibly interacts with other adjacent genes. The <i>TBP</i> gene encodes a transcription factor which is potentially related to cognitive development. <i>TBP</i> is linked to <i>PSMB1 </i>and <i>PDCD2 </i>in a conserved manner among mammals, suggesting a potential interaction between these genes. In conclusion, the 6q27 microdeletion is a complex syndrome with variable expressivity of brain malformations and intellectual disability phenotypes which are possibly triggered by the 4 genes described and adjacent genes susceptible to gene regulation changes.

Genotype–Phenotype Correlations for Putative Haploinsufficient Genes in Deletions of 6q26-q27: Report of Eight Patients and Review of Literature

“… Abbreviations: –, not present; +, present; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; CD, ciliary dyskinesia; DD, Development delay; dn, de novo; EDS, Ehlers-Danlos syndrome; EOPD, early-onset Parkinson disease; EP, episodes of psychosis; gw, gestational weeks; HK, horseshoe kidney; HL, hearing loss; IA, imperforate anus; ID, Intellectual disability; mac, macrocephaly; mat, maternal; MDKH, multicystic dysplastic kidney and hydronephrosis; nb, newborn; OCD, obsessive-compulsive disorder; p/m, bi-parental; pat, paternal; PDA, patent ductus arteriosus; sb, stillbirth; top, termination of pregnancy; VSD, ventricular septal defect. Note: Patients (Pts) were collected from this study (TS) and published reports, and number in parenthesis () refers to the patient number in TS and the reports; patients 1, 11, 13, 15, 18, and 20 were from the report of Peddibhotla et al (2015), 20 patient 2 was from Thakur et al (2018), 22 patient 3 was from Li et al (2011), 17 patient 4 was from Valduga et al (2010), 13 patient 5 was from Puvabanditsin et al (2020), 25 patients 6, 9, 22, 27, 28, 29, 31, 33, and 35 were from Conti et al (2013), 19 patients 7 and 8 were from Wadt et al (2012), 18 patient 10 was from Dupé et al (2011), 15 patient 14 was from Mosca et al (2010), 12 patient 19 was from De Cinque et al (2017), 21 patient 26 was from Hanna et al (2019), 24 patient 30 was from Rigon et al (2011), 14 patient 34 was from Gerber et al (2011), 16 and patient 36 was from Williams et al (2018). 23 …”

“… Note: Patients (Pts) were collected from this study (TS) and published reports, and number in parenthesis () refers to the patient number in TS and the reports; patients 1, 11, 13, 15, 18, and 20 were from the report of Peddibhotla et al (2015), 20 patient 2 was from Thakur et al (2018), 22 patient 3 was from Li et al (2011), 17 patient 4 was from Valduga et al (2010), 13 patient 5 was from Puvabanditsin et al (2020), 25 patients 6, 9, 22, 27, 28, 29, 31, 33, and 35 were from Conti et al (2013), 19 patients 7 and 8 were from Wadt et al (2012), 18 patient 10 was from Dupé et al (2011), 15 patient 14 was from Mosca et al (2010), 12 patient 19 was from De Cinque et al (2017), 21 patient 26 was from Hanna et al (2019), 24 patient 30 was from Rigon et al (2011), 14 patient 34 was from Gerber et al (2011), 16 and patient 36 was from Williams et al (2018). 23 …”

“…This literature search found 14 articles with 28 patients having a deletion of 6q26-q27. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Reported patients without cytogenomic mapping for the deletion, with large deletions extending to 6q25, and compound rearrangements involving other chromosomes were excluded. 26 27 …”

“…We also performed a literature review to evaluate the clinical and cytogenomic findings from 28 patients with a deletion of 6q26-q27. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 From this series of 36 patients, we defined genotype–phenotype correlations from prenatal to postnatal stages and two critical regions with putative haploinsufficient genes and other candidate morbid genes. These results provided evidence for diagnostic interpretation, genetic counseling, and clinical management of patients with deletions of 6q26-q27.…”

Genetic causes underlying grey matter heterotopia

“…PVNH has been noted in several patients (figure 1), but does not seem in common feature in this syndrome (22,23). A deletion involving chromosome region 6q27 is associated with a pattern of structural brain malformations with abnormalities of the corpus callosum, cerebellum and hippocampus, predominantly posteriorly enlarged ventricles or hydrocephalus, and scattered PVNH (figure 2) (24)(25)(26)(27)(28). Not all features are present in every patient and no recognizable facial gestalt is associated with this syndrome.…”