DeSanto-Shinawi Syndrome: First Case in South America

Abstract

Pathogenic variants in WAC are uncommon causes of developmental delay and neurobehavioral phenotypes. The clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features that were recently delineated as DeSanto-Shinawi syndrome (DESSH; OMIM 616708). Additional clinical features include hypotonia, hearing and vision abnormalities, gastrointestinal problems, and behavioral difficulties. Here, we report a case of a 4-year-old Colombian male patient with typical dysmorphic facial features, developmental delay, hyperactivity, and recurrent respiratory infections. His immune workup revealed hypogammaglobulinemia, and clinical exome sequencing revealed a novel intronic variant in WAC (c.1437+1G>A). To the best of our knowledge, this is the first case of DESSH in South America, underlining the accumulating evidence of the significant role of WAC haploinsufficiency in neurobehavioral phenotypes. Although this report suggested the potential involvement of WAC in immune regulation, additional reports are required to confirm our observations.

A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

“…The first few cases of WAC-related ID were briefly reported from exome/genome sequencing studies of family trios with ID or ASD and, to date, about 60 diverse WAC mutations have been reported in public databases (Supplementary Table S2). However, an extensive clinical description has been reported in the literature for only 20 patients [7,8,10,11]. Major features are summarized in Table 1.…”

“…Common dysmorphic features include a squared shaped face with broad/prominent forehead, depressed nasal bridge and bulbous nasal tip, deep set eyes, long palpebral fissures, and wide mouth with a broad chin. To date, a detailed description of the clinical phenotype has been reported only for 20 individuals with WAC-related ID [7][8][9][10][11]. All of them, except for one family with presumed parental gonadal mosaicism, have de novo pathogenic loss of function (LoF) variants.…”

A Case of DeSanto-Shinawi Syndrome in Bahrain with a Novel Mutation

“…In addition to these functions, WAC also plays a role in pathogen recognition and antigen presentation. Accordingly, an interesting hypothesis was put forth by Vanegas et al regarding the association of WAC haploinsufficiency, recurrent infections, and hypogammaglobulinemia seen in the case reported by them [ 4 ]. The patient we report was treated for multiple respiratory and skin infections, and this warranted an immunological workup, but the results turned out to be normal.…”

“…DeSanto-Shinawi syndrome (DESSH, OMIM 616708) is an autosomal dominant genetic condition caused by loss-of-function mutations in WAC and is characterized by a multitude of dysmorphic features such as a broad forehead, bulbous nasal tip, posteriorly rotated ears, deep-set eyes, brachycephaly along with behavioral abnormalities, and intellectual disability [ 1 – 4 ]. Twenty cases have been reported with DESSH, and all have been identified to have a de novo mutation in the WAC gene [ 4 – 7 ]. Four additional individuals with a WAC de novo mutation have also been reported but do not have the full spectrum of physical findings as the previously reported twenty cases [ 8 , 9 ].…”

A murine Wac model exhibits phenotypes relevant to DeSanto-Shinawi Syndrome

“…DESSH was initially characterized by a combination of hypotonia, cranio-facial dysmorphic features, developmental delay and neurological/neuropsychiatric symptoms [1]. Neurological and neuropsychiatric symptoms include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and seizures [1][2][3][4][5]. Wac is considered a high confidence ASD risk gene due to the elevated genetic variants discovered in ASD populations [6].…”