Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature

Abstract

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan–Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin–Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital

“…This variant could be compatible with the diagnosis, as the patient presents tall stature, hemihypertrophy, ASD, and DI. However, hemihypertrophy has not been previously described in association with this disorder [41].…”

“…Regarding VUS with a possible pathogenic cause, it is worth mentioning that patient AUT195 has a variant in the SETD2 gene described in the literature regarding Luscan-Lumish syndrome (OMIM #616831), an overgrowth syndrome with which we have great clinical experience [41]. This variant could be compatible with the diagnosis, as the patient presents tall stature, hemihypertrophy, ASD, and DI.…”

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…Chromatin modifiers are closely related to neurodevelopment. Recently published studies have confirmed that patients with HMT SETD2 mutations present with intellectual disability, developmental delay, and skeletal system abnormalities as the main clinical manifestations [ 101 ]. However, mutations in the domain between HMT NSD1 exon 10 and 22 are associated with microcephaly [ 102 ].…”