Expansion and further delineation of the phenotype of SETD5
The SET domain containing 5 gene (SETD5) encodes the SET domain-containing protein 5 and has been reported to be associated with intellectual disability (ID), language delay, and dysmorphic features (1,2).
SETD5 is among the genes deleted in patients with 3p25.3-deletion syndrome (OMIM #613792) who present with encephalopathy, intellectual disability (ID), low birth weight, microcephaly, hypotonia, psychomotor and growth retardation, and facial dysmorphia including ptosis, telecanthus, down slanting palpebral fissures, and micrognathia (3).
Previously reported individuals with SETD5 alterations have been described with ID, psychiatric/behavioral anomalies such as autism (ASD) and stereotypic behaviors, and gastrointestinal abnormalities. Craniofacial abnormalities such as tubular nose with a broad nasal bridge and bulbous tip with anteverted nares, upslanting/down slanting palpebral fissures, long and smooth philtrum, thin upper lip, downturned corners of the mouth, and ear abnormalities have also been described (4)
Szczałuba et al recently reported the first inherited case of a pathogenic alteration in SETD5. The two brothers were reported with ID, triangular facies, micrognathia, abnormal ears and philtrum and additional variable features. The father (from whom the alteration was inherited) demonstrated only mild ID . The three carried a previously unreported alteration along with a FGFR1 alteration previously associated with Kallman syndrome (5)
We report the first patients with a SETD5 alteration with microcephaly (1 patient), a feature present in many individuals with the deletion syndrome containing SETD5.
§We also report the first cases with:
PROTECTIVE EFFECTS IN FEMALES: A son inherited the alteration from his mother who had similar craniofacial dysmorphism, bilateral postaxial polydactyly of her hands, but normal intelligence. Another female without cognitive delay.
LACK OF DYSMOPRHIC FEATURES: One proband with cognitive delays, skeletal abnormalities, and hand anomalies had no dysmorphic features.
Additional features present in this cohort include epicanthal folds and a low posterior hairline.
Review of the 12 cases in this cohort and 14 previously reported cases indicate that the majority of patients have dysmorphic features but the presentation is highly variable.
The phenotype of SETD5 appears more complex and variable than previously presented