Trisomy X syndrome with dystonia and a pathogenic SATB1 variant

Abstract

The widespread application of modern sequencing technologies has revealed an ever-growing number of novel genedisease associations and genotype-phenotype correlations. Sometimes, two different genetic abnormalities may occur in a single person and considerably confound the phenotype. Herein, we report on a patient with a known gonosomal numeric aberration, who was also found to carry a pathogenic point mutation in a new candidate dystonia-associated gene, SATB1. The patient is a 18-year-old girl with an intellectual disability (IQ 79); various behavioral (trichotillomania, obsessivecompulsive disorder), emotional (separation anxiety), and language (developmental dysphasia, elective mutism) problems; and clumsiness of the hands since early childhood. She comes from a nonconsanguineous marriage, and her perinatal and family history were normal. She went to a special elementary school. At the age of 14 years, based on the clinical picture, a karyotyping analysis was performed, which determined a trisomy X syndrome (TXS). In addition to this, the patient has b e en d i a gno s ed w i t h ameno r r h e a ; g i g an t i sm ; hyperprolactinemia; kyphoscoliosis; pes planus; joint hypermobility; and sarcoidosis with lung, skin, eye, and joint involvement. She had been referred to us for a manifestation of tremor. Bilateral hand tremor started in her early childhood and was not troublesome except for during stress episodes. However, it has changed its intensity and character over the past two years. On examination, she exhibited tall stature (185 cm), elective mutism, asymmetric bilateral irregular resting and postural tremor of the hands with dystonic posturing (much worse on left side), and overflow dystonia. A decreased armswing and hand stereotypies were noted during gait. The rest of the examination was unremarkable (see Video 1). A brain MRI revealed only a few punctiform frontal white matter changes. A DaT-SCAN, EEG, and diagnostic blood workup including ceruloplasmin, vitamins, and paraneoplastic antibodies were found to be normal. Treatment with levodopa and propranolol were ineffective. As dystonia has not been reported as a part of the clinical spectrum associated with TXS, we suggested an alternative etiology and applied whole-exome sequencing to the patient and her unaffected parents. With the use of wholeexome sequencing, we followed current recommendations for the assessment of neurodevelopmental disorders [1]. This analysis identified a de novo nonsense variant affecting the last exon of SATB1 (NM_001131010:c.1924C>T, p.Arg642*) as the only suspicious finding. The variant was absent from genomic control datasets (gnomAD, in-house exomes) and predicted to be deleterious (CADD score of 38). According to the American College of Medical Genetics and Genomics guidelines, the variant qualified as a “pathogenic” allele (“PVS1, PS2, PM2, PP3”) [2]. The Special AT-rich Sequence Binding Protein 1 (SATB1) is a chromatin organizer and transcription factor which regulates differentiation, proliferation, and apoptosis through its effect on the expression of evolutionary conserved sets of genes. As an oncogene, SATB1 was found to be overexpressed in numerous malignancies and plays a role in tumorigenesis [3]. Moreover, SATB1 is considered a recently defined risk factor for Parkinson’s disease [4]. Loss of SATB1 causes activation of cellular senescence in dopaminergic neurons both in mice and humans. The persistence of senescent cells in tissues leads to local inflammation, harming of surrounding cells, and f ina l ly ag ing , a charac te r i s t i c fea tu re of many * Ján Necpál [email protected]