Table 3 Clinician and patient advocate confirmation of key symptom relevance

Seizures

Clinicians

4/5

1/5

5/5

“Um, seizures are very important 'cause there is a difference of a priority from having a seizure and being safe and having it… you know, putting a person in jeopardy versus, um, say, uh, not being able to, um, walk correctly but use an aid.”

“Yeah, mo- most of the symptoms are gonna be seizures and, and sleep.”

PAs

5/5

0/5

5/5

Sleep

Clinicians

2/5

3/5

5/5

“Yeah, difficulty sleeping, uh, limited in their duration of sleep. If they have, yes, that's an often a common issue.”

“The sleep can be really hard, because if they aren't sleeping at night, they'll often fall asleep during the day. And then, they can't have a normal life, because they have to sleep during the day, and they have to miss out on […] school, or activities, or different things.”

PAs

5/5

0/5

5/5

Nonverbal communication

Clinicians

2/5

3/5

5/5

“Some of them will be nonverbal, you know, but will go on to learn, uh, very effectively at communicating sign language. And others will overcome, you know, that and it really just depends on the severity at that point.”

“The communication part is very big because um, unless they- they're… are given outside ways to do that using a communication device or something, they have no way to indi- indicate pain, tell you what happened when they weren't in front of your eyes, um, tell you what's bothering them when they have anxiety and um, the fine motor problems and the hypermoticity really um, limit the amount of sign language that Angelman people can do well.”

PAs

3/5

2/5

5/5

Verbal communication

Clinicians

5/5

0/5

5/5

“There's so many things, it [developmental delays] could be from, uh, hand gestures, and their verbal and nonverbal communications, depending on how young they are […] whether they mumble or try to speak, and, it's, I mean, a lot of factors.”

“There are some kids out there that are, are able to say a few words, um, very basic words, but a few words or you know, a, a different way of communicating that is not verbal. So I mean the hope is that there is, you know, that there can be some verbal words that are used, used, but if not that there is some sort of forms, um, or outlets to allow them to communicate.”

PAs

2/5

3/5

5/5

Fine motor

Clinicians

2/5

3/5

5/5

“They have problems with motor skill- skills, especially fine motor skills, and sometimes gross motor skills, th- those, and, and, they're just, they have got developmental problems, uh, which starts right around, uh, really noticeable from 6 months on, I’d say, and especially getting closer to being a toddler.”

“Yes, fine, fine motor skills is, is, uh, absolutely up there as far as, um, uh, a symptom of, of Angelman syndrome. […] Be it taking a block and putting on top, top of another one, or going to a… I’m thinking of everyday life, going to a door and turning the handle to open the door. It's difficult for, for Angelman, uh, uh, people to do that.”

PAs

1/5

4/5

5/5

Gross motor

Clinicians

5/5

0/5

5/5

“Basically it’s just about crawling, um, walking, um, able to hold balance, basically, delays that a child with difficulty can start, you know, crawling, walking, running, where this child may have complete delays.”

“Um, a lot of the kids start walking by the age of 4, um, but they still can have difficulty kind of walking smoothly and running properly or, um, balancing, you know, when there's a curbing or steps, so gross motor skills in the school-age kids are not as worrisome as the fine motor, really. But I mean, it still is a problem, and then as the kids get older, after the age of 12, their gross motor skills get worse. So in the age that you spoke of, I think the gross motor skills are, are definitely important, uh, but maybe not quite as important as some of the other things.”

PAs

2/5

3/5

5/5

Cognition

Clinicians

1/5

4/5

5/5

“Yes. Significant cognitive the, uh, uh, abilities they tend to. And that persists even as they get older.”

“Um, that's, I mean, if you look at the, the population most, uh, Angelman is, is a deletion and, and their cognitive ability to, you know, really to learn is, is poor. Um, learning colors or, or symbols and, and matching them. They might be able to do it one week and then not the next week.”

PAs

3/5

2/5

5/5

Maladaptive behaviors

Clinicians

2/5

3/5

5/5

“It's just as they get a little older we look at their behaviors as far as, uh, what's appropriate, uh, behavioral patterns for their age-appropriateness. Uh, we notice, uh, possibly hyperactivity, uh, whether they're clapping their hands, whether they're laughing and over ha- overly happy, or in, we notice if some of their, uh, some of their be- um, behaviors are overly repetitive. You know, you know, and depending on how old they are, up until 12, we notice that sometimes they refuse to, uh, engage or particip- uh, participate […] in activities.”

“Um, the biggest struggles I see are seizures and behavior. […] Um, the aggression, hair pulling, pinching, kicking, biting. Those kinda things.”

PAs

3/5

2/5

5/5

Caring for self

Clinicians

1/5

4/5

5/5

“Some will get to the point where they can easily, you know, dress themselves, they might struggle with fine motor skills, buttoning things, zipping things, um, where others will have to have complete assistance.”

“And then also just daily living skills, like brushing teeth, eating, buttoning, um, buttons, um, m- manipulating, I mean using a pencil or a pen. So most of the kids really have difficulty with all of those things.”

PAs

3/4^a

1/4^a

4/4^a