Klinefelter syndrome mosaicism in boys with neurodevelopmental disorders: a cohort study and an extension of the hypothesis

Abstract

Background Klinefelter syndrome is a common chromosomal (aneuploidy) disorder associated with an extra X chromosome in males. Regardless of numerous studies dedicated to somatic gonosomal mosaicism, Klinefelter syndrome mosaicism (KSM) has not been systematically addressed in clinical cohorts. Here, we report on the evaluation of KSM in a large cohort of boys with neurodevelopmental disorders. Furthermore, these data have been used for an extension of the hypothesis, which we have recently proposed in a report on Turner’s syndrome mosaicism in girls with neurodevelopmental disorders. Results Klinefelter syndrome-associated karyotypes were revealed in 49 (1.1%) of 4535 boys. Twenty one boys (0.5%) were non-mosaic 47,XXY individuals. KSM was found in 28 cases (0.6%) and manifested as mosaic aneuploidy (50,XXXXXY; 49,XXXXY; 48,XXXY; 48,XXYY; 47,XXY; and 45,X were detected in addition to 47,XXY/46,XY) and mosaic supernumerary marker chromosomes derived from chromosome X (ring chromosomes X and rearranged chromosomes X). It is noteworthy that KSM was concomitant with Rett-syndrome-like phenotypes caused by MECP2 mutations in 5 boys (0.1%). Conclusion Our study provides data on the occurrence of KSM in neurodevelopmental disorders among males. Accordingly, it is proposed that KSM may be a possible element of pathogenic cascades in psychiatric and neurodegenerative diseases. These observations allowed us to extend the hypothesis proposed in our previous report on the contribution of somatic gonosomal mosaicism (Turner’s syndrome mosaicism) to the etiology of neurodevelopmental disorders. Thus, it seems to be important to monitor KSM (a possible risk factor or a biomarker for adult-onset multifactorial brain diseases) and analysis of neuromarkers for aging in individuals with Klinefelter syndrome. Cases of two or more supernumerary chromosomes X were all associated with KSM. Finally, Rett syndrome-like phenotypes associated with KSM appear to be more common in males with neurodevelopmental disorders than previously recognized.

Somatic mosaicism in the diseased brain

“…Recent studies have additionally supported the idea that somatic mosaicism in the diseased brain may be a mechanism for neurodevelopmental and neurodegeneration disorders [132][133][134]. Furthermore, clinical (neurodevelopmental) cohorts repeatedly demonstrate high rates of somatic mosaicism [135][136][137], which may be seen as a mechanism for the disease or a target for therapeutic interventions [23,138]. In this context, it is to mention an intriguing mechanism for brain-specific chromosome instability and/or aneuploidy termed chromohelkosis (chromosome ulceration or open wound), which results from the co-occurrence of non-mosaic and mosaic chromosome imbalances caused by a susceptibility to genome instability and a genomic rearrangement [139].…”

KIF2C affects sperm cell differentiation in patients with Klinefelter syndrome, as revealed by RNA‐Seq and scRNA‐Seq data

“…Klinefelter syndrome is an important cause of non‐obstructive azoospermia (NOA) and oligospermia, which is accompanied by impaired spermatogenesis, with 90% of patients presenting with azoospermia and 10% with severe oligospermia [ 19 , 20 ]. Furthermore, the effects of KS mosaicism may not be limited to germ cells；Ivan scholars [ 21 ] had found that KSM may be a factor in the pathogenic cascade in psychiatric and neurodegenerative disorders, particularly in cases where two or more X chromosomes are overrepresented. Moreover, mosiaicism is likely to be tissue specific [ 22 ], and therefore our focus in this study was primarily on single‐cell sequencing of testicular tissue.…”

The continuing Conundrum regarding MECP2 variants in Males

“…Adding to the confusion, the presence of classic RTT in males with MECP2 variants and X-chromosome mosaicism is well-documented, either due to somatic mosaicism or in association with Klinefelter syndrome, a 47XXY chromosomal disorder. This has been documented since MECP2 was first associated with RTT [21][22][23].…”