Thursday, October 6, 2016

Access for DNA sequencing

When Nic Volker was 2, his mother discovered an abscess on his rectum, and soon after, whenever he’d eat, his body would punish him by forming holes in his intestine. The once-healthy little boy’s condition led to a colectomy and mystified scientists for years until 2009, when he underwent DNA sequencing, which was then an emerging technology. Although the feat was a triumph for medicine, the trials that preceded the test— more than 800 days in the hospital, 172 surgeries, over 10 bouts of sepsis, countless medications and meetings with dozens of specialists— took a toll on Nic, who has recovered, but copes with seizures, developmental delays, anxiety and trauma…

“It’s a success story with sequencing, but what about if other kids in other families could get this done sooner? Then, you wouldn’t have to go through what Nic had to go through or what our family had to go through,” Amylynne Santiago Volker, Nic’s mother, told

As scientists continue to study the genome and strive to improve sequencing, Amylynne is fighting to expand access to the technology and potentially help the estimated 10 percent of Americans who suffer from a rare disease for which there is no diagnosis. She’s met with legislators, including Speaker of the House Paul Ryan twice, to propel the bill, the 21st Century Cures Act, which would offer funding for various health initiatives, rare diseases among them. She’s part of a group called Cures Coalition that’s lobbying Congress to pass the bill. As is, the legislation does not propose a specific amount of funding for DNA sequencing.

Already, thanks to more scientists using DNA sequencing, its cost has fallen from the $100,000 the Volkers paid to sequence only part of Nic’s genome to $6,500 to sequence an individual’s entire genome…

After Amylynne discovered the abscess on Nic’s rectum, doctors brushed it off as an innocuous wound. But when the abscess eventually burst after antibiotic treatment, the wound refused to heal and Nic began losing weight rapidly, at one point dipping to nearly 17 pounds. Doctors diagnosed him with failure to thrive, and he was worked up for Crohn’s disease, a condition usually more common in teenagers than in toddlers.

Traditional treatments didn’t work, and what followed was a slew of doctor’s appointments and surgeries, as well as days in the hospital where Nic was hooked up to an NG tube wired down his esophagus in an attempt to nourish his body.

But the more doctors fed him, the more Nic’s health declined.

“You could see that he was always in pain when he ate, but doctors kept thinking he wasn’t getting enough food,” Amylynne said. “Later, they found out they were killing him.”

In the end, 15 gastroenterologists weighed in on Nic’s case, but at the time, the one he was seeing said there was nothing he could do, Amylynne said.

That’s when Amylynne began researching more therapies and assembling what she called “a dream team of doctors” to try to save her son.

“I just wouldn’t listen to them, so I relied on my faith,” said Amylynne, who is a born-again Christian.

By January 2009, when he was about 4, Nic became completely line dependent for food and used a wound vac to avoid infection and sustain his life. In April, he underwent the colectomy, a procedure doctors weren’t sure he’d survive but had the potential to heal him. Nic only got sicker.

“’All we’re doing is keeping him alive for as long as we can,’” Amylynne recalled Nic’s surgeon saying…

After the medical college [Medical College of Wisconsin]agreed to move forward and passed proper regulatory measures, Amylynne and Jacob had to figure out how they were going to pay for the sequencing. At the time, sequencing Nic’s entire genome would have cost about $1 million. But doing only 1.5 percent of the genome, called exome sequencing, was cheaper. They ended up going with that option in July and paying $100,000, which was gathered in donations…

“I was told it could take up to three years; we were told we may not find anything,” Amylynne recalled, “but it ended up being just a few months, I believe, and it was November when I got a phone call.”

In February 2010, doctors confirmed that Nic had a one-in-a-billion genetic mutation, XIAP.

“They checked it with my blood and they basically told me that I gave it to him,” said Amylynne, choking back tears…

The mutation ultimately signaled apoptosis, a condition wherein Nic could not digest food properly and suffered inflammation, leading to more holes formed in his abdomen from which stool leaked. The diagnosis cleared doctors to do a bone marrow transplant, a procedure Amylynne had been requesting for years.

July 14, 2010, Nic received the transplant, which helped until about 28 days later, when he developed a brain infection. Available medications didn’t work to heal him, so Amylynne had to fight for her son again to obtain another drug, foscarnet, which the Food and Drug Administration had been taken off the market…

After spending numerous days in the hospital (Amy stopped counting at day 800), Nic is still recovering mentally and emotionally. The boy missed out on day care, pre-K and all but the last six weeks of kindergarten as he was required to be quarantined either in the hospital or at home while immunosuppressed…

Bioethicists and geneticists agree that in the far-off future, every child could undergo DNA sequencing, but experts like Jacob said children like Nic would be prioritized immediately if there was expanded access.

“What’s practical today is we really need to help the patients that have these undiagnosed diseases, and undiagnosed disease is often rare disease,” Jacob said, “and rare disease often sounds uninteresting, but rare is a medical condition— it means its less than 200,000 people with it.”…

Through her foundation, Amylynne wants to jump-start programming, such as scholarships and recreational camps, for children like Nic who have survived seemingly insurmountable diseases and still suffer trauma from their experiences, but don’t belong to established communities of survivors. Recently, Nic was diagnosed with post-traumatic stress disorder (PTSD).

“Having a rare disease doesn’t fit into the mold,” Amylynne said. “There are a lot of kids who have cancer, so there is a lot of programming for that, but [Nic] didn’t have cancer, so hopefully we can develop programming for those kids to fit in.”…

Although Nic continues to cope with trauma through therapy, the past few months have marked “the best summer he can remember,” Amylynne said.

The family goes to a local recreation club where Nic zooms down the big water slides, and recently, the Volkers celebrated Nic’s six-year bone marrow transplant anniversary by going to Great Wolf Lodge in Wisconsin Dells, Wisconsin, a park with water slides and hotels. He’s been able to do things he never has before, Amylynne said.

“Nic likes to quote a lot of TV shows and movies— from ‘Guardians of the Galaxy,’: ‘It’s been a tough run so far.’” He likes to say that all the time,” Amylynne said. “He really is a comeback kid.”


  1. Christiansen M, Ammann S, Speckmann C, Mogensen TH. XIAP deficiency and MEFV variants resulting in an autoinflammatory lymphoproliferative syndrome. BMJ Case Rep. 2016 Sep 28;2016.

    A 16-year-old boy of Caucasian ethnicity was evaluated for recurrent febrile episodes occurring during most of his life without establishment of any microbial aetiology. During febrile episodes he developed extensive splenomegaly, lymphadenopathy, anaemia, severe abdominal pain and general malaise. Lymph node biopsies demonstrated inflammation and sinus histiocytosis but no malignancy or granuloma. The patient underwent seroconversion for Epstein-Barr virus (EBV) infection during the hospitalisation. Genetic testing identified a hemizygous frameshift mutation in the X linked inhibitor of apoptosis (XIAP)-gene as well as variants in the MEFV gene indicating Familial Mediterranean Fever (FMF). XIAP expression was markedly reduced in the patient, while a functional assay assessing tumour necrosis factor (TNF)α production of monocytes in response to NOD2 stimulation displayed reduced activity. We suggest that the heterozygous MEFV variants and the hemizygous XIAP variant in combination triggered the prolonged and pathological inflammatory response to EBV infection.

  2. Jiang MY, Guo X, Sun SW, Li Q, Zhu YP. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report. Exp Ther Med. 2016 Sep;12(3):1341-1344.

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency.

  3. Girardelli M, Arrigo S, Barabino A, Loganes C, Morreale G, Crovella S, Tommasini A, Bianco AM. The diagnostic challenge of very early-onset enterocolitis in an infant with XIAP deficiency. BMC Pediatr. 2015 Dec 15;15:208.

    Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).
    We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.
    Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.