Dominic and Bridget Nuccitelli

Dominic and Bridget Nuccitelli both passed away in infancy after cardiorespiratory arrest, Dominic in 2001 and Bridget in 2007. Their development had been slow, they had low muscle tone, making them somewhat "floppy" and neither gained weight well. Each had distinctive features—such as Bridget having multiple birthmarks, large soft spots on the top and back of her head, and a very small jaw (micrognathia). Despite these, doctors hoped they just had a slight delay and that they would catch up with their peers, as they still appeared somewhat in normal range on most counts. Since Bridget was born prematurely, that was thought to account for her delays.

At times, though, they were listless and became more floppy. Dominic's physicians in the ICU suggested he might have a mitochondrial disease, and one mentioned a specific mitochondrial disorder known as Barth syndrome. After Bridget's crisis event, doctors were more suspicious of a mitochondrial or possibly metabolic disorder.

Six living siblings each have varying symptoms that are chronic but not currently life-threatening; their parents, Marie and Chris Nuccitelli, call them "quirks." The children's symptoms include hypotonia, motor difficulties, temperature regulation issues, developmental delays, sleep disturbances and immune deficiencies. One son has leg, neck and shoulder dystonia—muscle tightness that gave the appearance one side of his body had grown taller than the other. A daughter has milder dystonia, most often noticed in her hands, aggravated by writing. Several siblings have neurologic symptoms in response to viral infections. A son has multiple food allergies and, along with three sisters and Marie, eosinophilic esophagitis, an allergic reaction that inflames the esophagus. The same son and another daughter have micrognathia, macrocephaly (an enlarged head) and difficulty swallowing. Marie and Chris have various symptoms, too.

It's been hard finding a doctor that feels able to care for them, as one specialist's field of expertise often doesn't cover all the issues. The result is a lot of referrals. "We get bounced around a lot," says Marie. "I can't even keep track any more of all the doctors we've seen." Many of the specialists suspect a metabolic or mitochondrial DNA abnormality, because these can cause a broad range of symptoms of variable severity. However, mitochondrial DNA and metabolic tests have thus far come back conclusively negative.

The family hopes the CLARITY Undiagnosed Challenge will have more to say about possible mitochondrial mutations. If mutations are found in mitochondrial DNA (as opposed to DNA in the cell nucleus), the family "quirks" would only be passed on by the girls, not the boys. "My dream would be just to know, 'this is how your children died, this is how it may or may not be affecting the rest of you,'" Marie says. "There's always that question of, 'is there going to be another crisis event? Is there a day when another one of my children stops breathing?' For me it's important to have a genetic answer that's evidence-based. We wouldn't have to keep doing all these tests that are stressful and taxing financially."

What CLARITY Undiagnosed found

Sequencing of Dominic, Bridget, their parents and one sister identified genetic alterations, or variants, in three genes (CACNB2, DSP and CSRP3) that have been linked to heart arrhythmias. Arrhythmias can vary in severity, with the most severe cases resulting in sudden cardiac death. Marie carries two of these variants and Chris has one; Dominic and Bridget each inherited one variant from each parent. The two affected genes in Dominic and Bridget are known to be involved in ion channels responsible for sodium and calcium flow in and out of cells, which can regulate the heart's rhythm. All three findings are considered variants of uncertain significance (VUS) since it hasn't been established whether they actually alter the genes' function, or are benign changes in the genes.

Marie and Chris are interested in investigating the family's cardiac health further, noting that they and two of their sons had previously been found to have unusual patterns on EKGs. The boys were sent for echocardiograms, but beyond that they were not referred for further follow-up.

In addition to the heart-related genes, a variant was found in the gene TNFRSF13B, known to be involved in common variable immune deficiency (CVID), a group of disorders that impair the immune system. This variant could potentially explain the IgA deficiency in two children, as well as the eosinophilic esophagitis (affecting Marie and four children), but without further testing its effect on gene function is unclear and it is still considered a VUS.

Investigations of a genetic cause for the dystonia in two of the children, as well as other family symptoms, found no variants of potential relevance.

Marie and Chris feel participating in the Challenge was worthwhile, even though it yielded no definitive answers. "It gave us some things that are a little more substantive to consider, rather than just guessing," says Marie. And as Chris put it, "We're still lost in the wilderness, but now we have a compass so we have a little bit better idea of where we're going."

The family now has the opportunity to enroll in the Manton Center study to investigate how the variants discovered by the challenge affect the genes' function.