Attitudes Toward Updated Genetic Testing Among Patients with Unexplained Mismatch Repair Deficiency

Individuals who have colorectal cancer (CRC) or endometrial cancer (EC) displaying loss of immunohistochemical (IHC) staining of one or more mismatch repair (MMR) proteins without a causative germline mutation are said to have unexplained mismatch repair deficiency (UMMRD, also known as mutation-negative Lynch syndrome). Comprehensive genetic testing that could potentially further clarify Lynch syndrome (LS) carrier status is essential to provide tailored screening guidelines to affected individuals and their family members; however, patient understanding of the potential impact of updated genetic testing for LS is unclear. This study aimed to evaluate the interest in and perceived impact of updated genetic testing among individuals with UMMRD at a tertiary academic center. A survey evaluating interest in updated genetic testing was mailed to 98 potential participants, and an electronic health record review was completed for the 31 individuals who returned the survey. Results indicate that this population is highly interested in updated genetic testing, and their perceived impact is primarily for family members to have appropriate testing and screening options. Updated risk assessment and genetic counseling, along with a discussion of the benefits and limitations of genetic testing, is essential as the understanding of potential causes of UMMRD evolves. Updated genetic counseling may allow patients with UMMRD to better understand the interpretation of their tumor and germline testing, as well as the impact of comprehensive genetic testing for themselves and their family members

Do Dogs Experience Cognitive Dissonance?

Cognitive dissonance, the mental discomfort experienced when a person hold contradictory beliefs and/or behaviors, has been studied through the effort justification paradigm – wherein people prefer a reward more when they have put more effort towards it. Contrast theory, a behaviorist approach, says this preference is due to the greater difference between participant’s starting and ending state. Dogs participated in a version of the effort justification paradigm designed to test if they experience cognitive dissonance. They alternated between two versions of a task: hearing either a severely or mildly annoying noise before receiving one of two differently colored dog treats from a “treat machine”. Afterwards, they were given a preference test to see if they formed a preference for the treat associated with the severely annoying noise (consistent with the effort justification paradigm). One explanation for the effort justification effect is contrast theory, which was eliminated by assigning dogs to either a contingent or non-contingent treatment. In the contingent treatment, noises preceded treats predictably and the noises and treats both came from the treat machine. In the non-contingent treatment, noises randomly preceded the treats and noises came from the other side of the room. Dogs’ preferences will be explored in light of cognitive dissonance and contrast theories

Kagami-Ogata syndrome in a patient with 46,XX,t(2;14)(q11.2;q32.2)mat disrupting MEG3

Kagami-Ogata syndrome (KOS14) is a rare imprinting disorder characterized by a unique constellation of phenotypes including bell-shaped small thorax with coat-hanger appearance of the ribs. We encountered an African American female infant with KOS14 phenotype and 46,XX,t(2;14)(q11.2;q32.2)mat. After excluding upd(14)pat and an epimutation (hypermethylation) and a deletion affecting the maternally derived 14q32.2 imprinted region, we performed whole-genome sequencing, revealing that the translocation was generated between noncoding region at 2q11.2 and intron 6 of MEG3 at 14q32.2. Subsequent Sanger sequencing for the fusion points showed that the chromosomal fusion on the der(2) chromosome occurred between Chr2:102,193,994 (bp) and Chr14:101,314,628 (bp) in association with an insertion of 5-bp segment of unknown origin and that on the der(14) chromosome took place between Chr14:101,314,627 (bp) and Chr2:102,193,995 (bp) in association with an insertion of 1-bp segment of unknown origin (according to GRCh37/hg19). The results, together with the previous data in patients with KOS14, imply that the MEG3 disruption by 46,XX,t(2;14)(q11.2;q32.2)mat caused silencing of all MEGs including RTL1as and resultant excessive RTL1 expression, leading to the development of KOS14. To our knowledge, while Robertsonian translocations involving chromosome 14 have been reported in KOS14, this is the first case of KOS14 caused by a chromosomal translocation involving the 14q32.2 imprinted region

AHDC1 missense mutations in Xia-Gibbs syndrome

Xia-Gibbs syndrome (XGS; MIM: 615829) is a phenotypically heterogeneous neurodevelopmental disorder (NDD) caused by newly arising mutations in the AT-Hook DNA-Binding Motif-Containing 1 (AHDC1) gene that are predicted to lead to truncated AHDC1 protein synthesis. More than 270 individuals have been diagnosed with XGS worldwide. Despite the absence of an independent assay for AHDC1 protein function to corroborate potential functional consequences of rare variant genetic findings, there are also reports of individuals with XGS-like trait manifestations who have de novo missense AHDC1 mutations and who have been provided a molecular diagnosis of the disorder. To investigate a potential contribution of missense mutations to XGS, we mapped the missense mutations from 10 such individuals to the AHDC1 conserved protein domain structure and detailed the observed phenotypes. Five newly identified individuals were ascertained from a local XGS Registry, and an additional five were taken from external reports or databases, including one publication. Where clinical data were available, individuals with missense mutations all displayed phenotypes consistent with those observed in individuals with AHDC1 truncating mutations, including delayed motor milestones, intellectual disability (ID), hypotonia, and speech delay. A subset of the 10 reported missense mutations cluster in two regions of the AHDC1 protein with known conserved domains, likely representing functional motifs. Variants outside the clustered regions score lower for computational prediction of their likely damaging effects. Overall, de novo missense variants in AHDC1 are likely diagnostic of XGS when in silico analysis of their position relative to conserved regions is considered together with disease trait manifestations.Among >270 individuals diagnosed with Xia-Gibbs syndrome (XGS; MIM: 615829), almost all have de novo “truncating” mutations in AHDC1. There are now also 10 reports of XGS arising from de novo missense AHDC1 mutations. We mapped these to the AHDC1 protein domain structure and identified two critical, sensitive regions