Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance

Abstract

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Genetic variations on SETD5 underlying autistic conditions

“…The reported mutation expanded the phenotypic spectrum of mutations previously found in the SETD5 gene, allowing the inclusion of the early‐onset epileptic encephalopathies (EOEEs) as a novel condition associated with SETD5 mutations (Kobayashi et al, ). This same insertion was found as a de novo event in other three patients: two males and one female (Powis et al, ). In the first male patient, with 3 years old, the variant was associated with developmental delay and dysmorphic features.…”

“…Among the LoF SNVs in SETD5 , four correspond to nonsenses variants as follows (all genomic coordinates are based on human reference genome, build Hg19): NM_001080517:c.1195A > T (p.Lys399*), NM_001080517:c.1333C > T (p.Arg445*), NM_001080517:c.1866C > G (p.Tyr622*) and NM_001080517:c.3001C > T (p.Arg1001*). The mutation c.3001C > T, was also reported in a male with ten years old with developmental disability and dysmorphic features (Powis et al, ). In the same study, in patients with developmental delay, behavioral/psychiatric issues, it was found the following likely LoF SETD5 de novo variants in SETD5 : NM_001080517:c.1655_1656insA, NM_001080517:c.1783‐2A > T, NM_001080517:c.582dupA (p.Ala195Serfs*), NM_001080517:c.1967delT (p.Leu656*) and NM_001080517:c.3246delT (p.Ala1083Leufs*61).…”

“…Grozeva et al () was the first to show a phenotypic resemblance between individuals with 3p25 deletion and mutations in SETD5 gene, sufficient to cause ID. Recently, 14 individuals with SETD5 mutation were described demonstrating the variable features in phenotypes, such as facial dysmorphism (Powis et al, ).…”

“…Other two cases of inherited SETD5 alterations were analyzed (Powis et al, ). In a male patient, with global developmental delay, hypotonia, mild spastic diplegia, dysarthria, and anxiety, received from his unaffected mother, the frameshift variant NM_001080517:c.1655_1656insA.…”

Developmental disorders with intellectual disability driven by chromatin dysregulation: Clinical overlaps and molecular mechanisms

“…The SET domain containing protein 5 ( SETD5 ) gene (MIM 615743) encoding a conserved methyltransferase expressed throughout the brain was already known to be the crucial determinant of the 3p25.3 deletion syndrome associated with ID, language delay and dysmorphic features (MR23, MIM 615761) . Recently, SETD5 loss‐of‐function mutations have been disclosed by diagnostic exome in a consistent cohort of patients expressing a highly variable phenotype, like the first reported familial syndromic ID cases . Interestingly, SETD5 mutations have been found in patients with suspected CdLS or KBG (Finelli, personal communication) (Table S3).…”