Summary: Researchers identify the genetic cause of intellectual disability in four male patients in record time.
Source: Baylor College of Medicine.
In a study published today in PLoS ONE, researchers report a rapid discovery linking small deletions on the X chromosome to a previously unrecognized cause of intellectual disability.
Using modern genomic databases and rapid electronic collaboration, the team traced intellectual disability in four males to overlapping deletions at Xp11.22 — a region not previously implicated in human disease. The work highlights how contemporary genetic tools and international communication can speed diagnosis and change lives.
Modern-day medical detective work
The investigation began during a routine clinic day for Dr. Daryl A. Scott, associate professor of molecular and human genetics at Baylor College of Medicine. One young male patient presented with intellectual disability, developmental delay, relative macrocephaly (enlarged head) and pronounced joint hypermobility. Initial laboratory testing revealed no known cause, but chromosomal microarray detected a small deletion on the X chromosome at band Xp11.22.
The deleted interval included only a few genes, among them MAGED1 and GSPT2. To evaluate whether those genes might explain the patient’s symptoms, Dr. Scott consulted functional data from model organisms. He found that mice lacking Maged1 show neurocognitive and neurobehavioral abnormalities — a clue that supported the hypothesis that loss of MAGED1 could contribute to the human phenotype.
To build evidence linking Xp11.22 deletions to the clinical features, Dr. Scott searched large genomic resources for additional affected individuals. A search of the DECIPHER database produced a match: a deletion closely resembling that of his patient. The database entry lacked clinical detail, so Dr. Scott contacted the submitting clinician, Dr. Alex Henderson of The Newcastle upon Tyne Hospitals, to learn more.
Simultaneously, Dr. Seema Lalani, associate professor of molecular and human genetics at Baylor and assistant laboratory director of cytogenetics at Baylor Genetics, searched a clinical database of more than 60,000 cases for similar deletions. Within hours these efforts produced results: Dr. Henderson reported two affected brothers carrying the same deletion, and Dr. Patricia Evans at the University of Texas Southwestern Medical School identified a fourth male with the overlapping Xp11.22 deletion and the same constellation of clinical findings.
Dr. Scott summarized the speed and impact of the work: “In a day’s work we identified four patients across two continents from three families and assembled the evidence within eight hours. None of the families had a prior explanation for these symptoms. Our findings enabled a genetic diagnosis.”
All affected males inherited the deletion from unaffected mothers. These mothers showed no clear clinical symptoms despite being carriers. This pattern is consistent with X-linked inheritance: mothers who carry the deletion have a 50 percent chance of passing the altered X chromosome to each child. Male offspring who inherit the deletion can show the syndrome, while female offspring may become carriers. This information provides families with concrete genetic counseling for future reproductive decisions.
Other contributors to the study include Christina Grau, Molly Starkovich, Mahshid S. Azamian, Fan Xia and Sau Wai Cheung. Funding was provided in part by the National Institutes of Health / National Institute of General Medical Sciences Initiative for Maximizing Student Development [R25 GM056929-16].
Source: Allison Huseman – Baylor College of Medicine
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research published in PLOS ONE titled “Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability,” authored by Christina Grau, Molly Starkovich, Mahshid S. Azamian, Fan Xia, Sau Wai Cheung, Patricia Evans, Alex Henderson, Seema R. Lalani, and Daryl A. Scott. Published online April 17, 2017.
Abstract
Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability
By querying a clinical database of over 60,000 individuals referred for array-based copy-number variation analyses alongside public genomic resources, investigators identified four males from three families with overlapping deletions at Xp11.22. The affected boys shared intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. The maximal shared deleted segment spans approximately 430 kb and includes two uncharacterized pseudogenes (CENPVL1 and CENPVL2) and two protein-coding genes: GSPT2 (G1 to S phase transition 2) and MAGED1 (MAGE family member D1).
Deletions of this ~430 kb region have not been previously associated with human disease. Although GSPT2 duplications have been observed in individuals with intellectual disability, loss-of-function effects for GSPT2 have not been characterized in humans or mouse models. MAGED1 has not previously been linked to human intellectual disability, but Maged1-deficient mice exhibit neurocognitive and neurobehavioral abnormalities. In all reported families, the deletion was inherited from an unaffected mother; X-inactivation studies in one carrier mother did not show evidence of skewing.
These findings support the conclusion that deletions of the ~430 kb region at Xp11.22 that include CENPVL1, CENPVL2, GSPT2 and MAGED1 define a distinct X-linked syndrome marked by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 likely contributes to the neurodevelopmental features observed in affected males.
Article: “Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability,” by Christina Grau et al., PLOS ONE, published online April 17, 2017.