Cytogenetic and Array-CGH Characterization of a Simple Case of Reciprocal t(3;10) Translocation Reveals a Hidden Deletion at 5q12

Abstract

Chromosome deletions, including band 5q12, have rarely been reported and have been associated with a wide range of clinical manifestations, such as postnatal growth retardation, intellectual disability, hyperactivity, nonspecific ocular defects, facial dysmorphism, and epilepsy. In this study, we describe for the first time a child with growth retardation in which we identified a balanced t(3;10) translocation by conventional cytogenetic analysis in addition to an 8.6 Mb 5q12 deletion through array-CGH. Our results show that the phenotypic abnormalities of a case that had been interpreted as “balanced” by conventional cytogenetics are mainly due to a cryptic deletion, highlighting the need for molecular investigation in subjects with an abnormal phenotype before assuming the cause is an apparently simple cytogenetic rearrangement. Finally, we identify PDE4D and PIK3R1 genes as the two major candidates responsible for the clinical features expressed in our patient.

Innovations in Phenotyping and Diagnostics Create Opportunities for Improved Treatment and Genetic Counseling for Rare Diseases

“…The strategies could end invasive diagnostic procedures, facilitate precision medicine, provide comprehensive care for patients, and augment genetic counseling for affected families. This Special Issue presents a collection of case studies in diagnostics [ 3 , 4 , 5 , 6 , 7 ], a report of workflow for undiagnosed DDs [ 2 ], a review [ 8 ] and examination of fragile-X-related behaviors [ 9 ], and a study of the mechanism of action of remimazolam in malignant hyperthermia [ 10 ]. These diverse articles are complemented by the article by Morganthau et al [ 11 ], who examine the benefits to care that can result from exposing medical students to DD patients.…”

“…The five case studies presented [ 3 , 4 , 5 , 6 , 7 ] illustrate the challenges associated with molecular diagnosis of DDs with phenotypic and genetic heterogeneity. For example, Thompson et al [ 3 ] report a case report of a child with features of hyperphosphatasia with neurologic deficit (HPMRS; MIM 239300) for whom variants of unknown significance were identified in two post-GPI attachment to protein genes, PGAP2 and PGAP3 , that underlie HPMRS 3 and 4.…”

“…By contrast, Khan et al [ 4 ] used in silico modeling to identify likely pathogenic biallelic variants in the NDST1 and METTL23 genes in intellectual disability (ID), and German et al [ 5 ] report an in silico workup of a novel FA2H variant identified as a homozygote in a male patient with a history that included childhood-onset progressive cognitive impairment and multisystem neurodegeneration consistent with FAHN/SPG35 upon brain imaging [ 5 ]. Case reports by Riviello et al [ 6 ] and Callamare et al [ 7 ] present evidence of chromosome structural changes that are associated with DD phenotypes. Riviello et al report large genomic structural variation in DD phenotypes.…”

“…Their findings highlight 2q37 microdeletion syndrome, a subtelomeric deletion disorder characterized by variable-sized deletions associated with short stature, facial dysmorphism, and features of autism spectrum disorder [ 6 ]. Callamare et al [ 7 ] report a balanced t(3;10) translocation and an 8.6 Mb 5q12 deletion, identified through array-CGH chromosome deletions, associated with a phenotype that includes postnatal growth retardation, intellectual disability, facial dysmorphism, and epilepsy. The PDE4D and PIK3R1 genes were identified as the two major candidates responsible for the clinical features.…”

“…The PDE4D and PIK3R1 genes were identified as the two major candidates responsible for the clinical features. The authors report that elements of the phenotype interpreted as “balanced” by conventional cytogenetics are mainly due to a cryptic deletion, highlighting the need for investigation prior to attributing cause to a cytogenetic rearrangement [ 7 ].…”