The clinical genetics group at our hospital holds a weekly conference to discuss patients recently seen by the clinicians and/or genetic counselors. I began attending this “post-clinic conference” when I moved here a year and a half ago. It’s been very educational for me, both in learning about some of the rare conditions affecting our pediatric patients and in how clinicians diagnose them.
In one of the first post-clinic conferences I attended (early September 2016), one of the clinicians presented a case of two sister with a severe disorder of unknown cause. They’ve apparently been followed by our team for a number of years. Both have severe intellectual disability, hypotonia, seizures, and a distinctive craniofacial appearance. Various clinical tests had been ordered, but none had provided a diagnosis.
It came up in the course of discussion that research exome sequencing had been performed on both girls and their (healthy) parents some time ago. There had been no finding at the time, but it was a few years back. Since I’d been recruited to work on rare disease genomics, I offered to revisit the analysis. We ran the case through our current pipeline, and found an interesting result:
Both sisters appeared to share a de novo (i.e. newly arisen) nonsense mutation in a gene called Additional Sex Combs Like 3 (ASXL3).
ASXL Mutations and Disease
A few years ago, Matt Bainbridge and his colleagues at Baylor had sequenced four unrelated patients with a disorder resembling Bohring-Opitz syndrome. Bohring-Opitz is a severe malformation disorder characterized by intrauterine growth retardation, severe intellectual disability, flexion deformities of the upper limbs, forehead hirsutism, and some craniofacial features. In 2011, a group in Europe had found that Bohring-Opitz was caused by de novo nonsense mutations in Additional Sex Combs Like 1 (ASXL1), which is required for maintenance of both activation and silencing of Hox genes.
The four unrelated patients in the Bainbridge study had de novo nonsense and frameshift mutations in ASXL3 (not ASXL1). Moreover, they were clinically distinct from Bohring-Opitz syndrome, with features including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay. OMIM entered it as a new syndrome in their database, and named it Bainbridge-Ropers syndrome (BRPS).
The two sisters from our case also had a de novo ASXL3 mutation. I was excited, and presented the finding at post-clinic in mid-September 2016. However, it got a lukewarm reception. Our mutation was in the middle of the ASXL3 gene (residue 1036), and predicted to truncate it to 46% of its wild-type length. The Bainbridge et al mutations were closer to the front of the gene (residues 404-466), which would remove a lot more. The phenotype was not a perfect match, either. Bottom line, they were unconvinced.
New Reports of Bainbridge-Ropers Syndrome
Over the next year, however, other groups identified de novo truncating ASXL3 mutations in other individuals with severe intellectual disability. A 2017 study by Balasubramanian et al described 12 previously unreported patients who were part of the DDD Consortium study (a large-scale intellectual disability cohort based in the UK). They delineated the six emerging common features of BRPS:
- Severe intellectual disability (11/12 patients)
- Poor or absent speech (12/12)
- Autistic traits (9/12)
- Distinct face, including arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures (9/12)
- Hypotonia (11/12)
- Significant feeding difficulties when young (9/12)
Our patients, you might recall, had all of these features. Also, the new studies reported de novo truncating mutations in the 1,000-1,100 region of the ASXL3 protein, similar to ours. With this new information, everyone was convinced and we started writing the paper. In the interim, one of our clinicians saw another (unrelated) patient who got a clinical diagnosis of BRPS.
A Chat with Bainbridge
In October 2017, I went to the ASHG annual meeting, where I bumped into Matt Bainbridge. We’ve known each other for years (since the 1,000 Genomes Project). Naturally, I gave him some trouble about having a syndrome named after him. Then I asked him about our patients’ mutation in ASXL3. He basically said, that’s right in the other cluster of disease-causing mutations.
I asked Matt if he thought it strange that our institution had three patients with a super-rare syndrome (<30 cases in the literature). He said that it’s probably more common than people realized. In fact, there might be as many as 200 cases diagnosed in the US.
“How do you know?” I asked.
“Because there’s a Facebook support group for the families,” he said. “In fact, they’d probably like to talk to your family, if they were interested, because most of their kids are younger.”
A Shared de novo Mutation
We reported the ASXL3 mutation to ClinVar in October 2017. By then, we’d performed independent Sanger sequencing of all four family members to confirm that it was de novo. The paper was accepted in December, and is available as an early access publication at Molecular Case Studies.
One obvious question is how two siblings born over a year apart could share the same de novo mutation if it arose after conception. Although this could theoretically happen by chance, the odds are extremely low. More likely, one of the parents is a mosaic for the mutation. The family declined further testing to determine the origin. They were not planning to have more children, anyway.
Unfortunately, there’s not much else we can do to help the family. However, we did refer them to the Facebook support group, and that may offer some support.