| Literature DB >> 33724192 |
Underrepresentation of Phenotypic Variability of 16p13.11 Microduplication Syndrome Assessed With an Online Self-Phenotyping Tool (Phenotypr): Cohort Study.
Jianqiao Li1,2, Margaret A Hojlo3,4, Joseph Gonzalez-Heydrich2,3,4,5, Catherine A Brownstein1,2,4,6, Sampath Chennuri7, Nitin Gujral7, Heather L Paterson1,2, Kent A Shefchek8, Casie A Genetti1,2, Emily L Cohn7, Kara C Sewalk9, Emily A Garvey3,4, Elizabeth D Buttermore10, Nickesha C Anderson11, Alan H Beggs1,2,6, Pankaj B Agrawal1,2,6,12, John S Brownstein7,6, Melissa A Haendel13, Ingrid A Holm1,2,6.
Abstract
BACKGROUND: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome.OBJECTIVE: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities.
METHODS: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis.
RESULTS: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome.
CONCLUSIONS: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes. ©Jianqiao Li, Margaret A Hojlo, Sampath Chennuri, Nitin Gujral, Heather L Paterson, Kent A Shefchek, Casie A Genetti, Emily L Cohn, Kara C Sewalk, Emily A Garvey, Elizabeth D Buttermore, Nickesha C Anderson, Alan H Beggs, Pankaj B Agrawal, John S Brownstein, Melissa A Haendel, Ingrid A Holm, Joseph Gonzalez-Heydrich, Catherine A Brownstein. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 16.03.2021.
Entities:
Keywords: 16p13.11 microduplication syndrome; copy number variation; digital health; genetics; human phenotype ontology; incomplete penetrance; online survey; phenotype; self-phenotyping; variable presentation
Year: 2021 PMID： 33724192 PMCID： PMC8074853 DOI： 10.2196/21023
Source DB: PubMed Journal: J Med Internet Res ISSN： 1438-8871 Impact factor: 5.428
Introduction
Methods
Recruitment
Phenotypr Survey Development
Figure 1Data entry for Phenotypr: relevant body system selection.
Figure 3Example of downloadable Phenotypr output.
Data Collection
Results
Table 1
Selected phenotypic features in 19 cases of 16p13.11 microduplication syndrome.
| Characteristic | Presented cases (patient numbers) | |||||||||||||||||||
|
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | |
| Age (years) | 10 | 3 | 8 | 2 | 14 | 12 | 14 | 5 | <1 | 7 | 6 | N/Aa | N/A | <1 | 18 | N/A | 3 | 9 | N/A | |
|
| ||||||||||||||||||||
|
| Growth abnormality | −b | − | +c | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Muscle weakness | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Tall stature | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Delayed speech | − | + | − | − | + | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Developmental regression | − | + | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Intellectual disability | − | − | − | − | + | − | − | − | + | − | − | − | − | − | − | − | − | − | − |
|
| Mild global DDd | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Specific learning disability | − | − | − | − | + | − | − | + | − | − | − | − | − | − | − | − | − | − | − |
|
| Dyslexia | − | − | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − |
|
| Cognitive impairment | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Hypotonia | − | − | − | + | − | + | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Poor fine motor coordination | − | − | − | − | + | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Tics | − | − | − | − | − | + | + | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Spasticity | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Dysarthria | − | − | − | + | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Anxiety | − | − | − | − | − | − | + | − | − | − | − | − | − | − | + | − | − | − | − |
|
| Depression | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − |
|
| ODDe | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − |
|
| ADHDf | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Seizure | − | − | − | − | − | − | − | + | − | + | − | − | − | − | − | − | − | − | + |
|
| ASDg/autistic behavior | − | − | − | − | + | + | − | − | − | + | + | − | − | − | − | − | − | − | − |
|
| Sleep disturbance | − | − | − | − | + | + | − | − | + | + | − | − | − | − | − | − | − | − | − |
|
| Parasomnia | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Behavioral abnormality | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | + |
|
| Impulsiveness or violence | − | − | − | − | + | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Aggression | − | − | − | − | + | − | − | + | − | + | − | − | − | − | − | − | − | − | − |
|
| Abnormal eating | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Self-mutilation | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Abnormal fear/anxiety | − | − | − | − | − | − | − | − | − | + | − | − | + | − | − | − | − | − | − |
|
| DMDDh | − | − | − | − | + | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Sensory impairment | − | − | − | + | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Hearing impairment | − | − | + | − | − | − | + | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Tinnitus | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Astigmatism | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Abnormality of the immune system | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Severe T-cell immunodeficiency | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Autoimmune antibody positivity | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Autoimmune encephalopathy | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Arrhythmia | − | − | − | − | − | − | − | − | − | − | − | − | − | − | + | − | − | − | − |
|
| Bradycardia | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Asthma | − | − | − | − | − | − | − | − | − | − | − | − | − | − | + | − | + | − | + |
|
| Chronic lung disease | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Neonatal respiratory distress | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Breathing dysregulation | − | − | − | − | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − |
|
| ||||||||||||||||||||
|
| Gastrostomy tube feeding in infancy | − | − | − | + | − | − | − | − | − | − | − | − | − | − | − | − | − | − | − |
|
| Dysphagia | − | − | − | − | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
|
| Feeding difficulties | − | − | − | + | − | − | − | − | − | + | − | − | − | − | − | − | − | − | − |
aN/A: not applicable.
bFeature absent or undisclosed.
cFeature present.
dDD: developmental delay.
eODD: oppositional defiant disorder.
fADHD: attention-deficit/hyperactivity disorder.
gASD: autism spectrum disorder.
hDMDD: disruptive mood dysregulation disorder.
Table 2
Comparison of the self-phenotyping cohort with the published cohort in the study by Allach El Khattabi et al [4].
| Feature | Cases in the study by Allach El Khattabi et al [ | Presented cases (N=19) | ||
| Hypotonia | 5/45 | 3/19 | ||
| Feeding difficulties | 5/45 | 2/19 | ||
|
|
|
| ||
|
| Developmental delaya | 32/45 | 3/19 | |
|
| Motor delayb | 19/45 | 2/19 | |
|
| Speech delay | 35/45 | 3/19 | |
|
| Learning disabilities | 30/45 | 2/19 | |
|
| ASDc | 24/45 | 4/19 | |
|
| Aggression | —d | 3/19 | |
|
| Anxiety | — | 4/19 | |
|
| Seizures | 10/45 | 3/19 | |
|
| Sleep disorderse | 8/45 | 4/19 | |
|
|
|
| ||
|
| Microcephaly | 1/23 | 1/19 | |
|
|
|
| ||
|
|
|
|
| |
|
|
| Long fingers | 1/22 | 1/19 |
|
|
|
|
| |
|
|
| Strabismus | 6/45 | 1/19 |
|
|
| Myopia | 4/45 | 1/19 |
|
|
| Amblyopia | 1/23 | 1/19 |
|
|
| Nystagmus | 1/22 | 1/19 |
|
|
|
| ||
|
| Immunodeficiency and autoimmune diseases | — | 2/19 | |
|
|
|
| ||
|
| Asthma | — | 3/19 | |
|
| Hypothyroidism | — | 1/19 | |
|
| Umbilical hernia | 1/22 | 1/19 | |
|
| Hearing lossf | 1/23 | 3/19 | |
|
| Abnormality of the male genitalia | 2 testicular ectopia and 1 cryptorchidism | 1/19 | |
aIncluding “developmental regression” and “mild global developmental delay.”
bCorresponding to “poor fine motor coordination.”
cASD: autism spectrum disorder.
dNot available.
eIncluding “sleep disturbance” and “parasomnia.”
fCorresponding to “hearing impairment.”
Table 3
Comparison of the self-phenotyping cohort with published case reports for anxiety, aggression, asthma, and immunological disorder phenotypes.
| Phenotype | Cases in the study by Hannes et al [ | Cases in the study by Ramalingam et al [ | Cases in the study by Nagamani et al [ | Cases in the study by Loureiro et al [ | Cases in the study by Allach El Khattabi et al [ | Cases in this study (N=19) |
| Anxiety | —a | 1/8b | — | 1/4c | — | 4/19 |
| Aggression | 1/5 | — | 1/10 | — | — | 3/19 |
| Asthma | — | — | — | — | — | 3/19 |
| Immunological disordersd | — | — | — | — | — | 2/19 |
aNot available.
bCo-occurring with autism spectrum disorder and attention-deficit/hyperactivity disorder.
cCo-occurring with autism spectrum disorder and hyperactivity.
dIncluding “abnormality of the immune system,” “severe T-cell immunodeficiency,” “autoimmune antibody positivity,” and “autoimmune encephalopathy.”
Discussion
Principal Findings
Limitations
Comparison With Prior Work on 16p13.11 Microduplication
Conclusions
65 in total
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