Journal of Neural Transmission (2023) 130:459–471

https://doi.org/10.1007/s00702-022-02569-3

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE

GenIDA: an international participatory database to gain knowledge

on health issues related to genetic forms of neurodevelopmental
disorders
Pauline Burger1,2,3,4 · Florent Colin1,2,3,4,5 · Axelle Strehle1,2,3,4 · Timothée Mazzucotelli1,2,3,4 · Nicole Collot1,2,3,4 ·
Romain Coutelle6,7 · Benjamin Durand8 · Arianne Bouman9 · Daphna Landau Prat10,11,12 · Tjitske Kleefstra9,13 ·
Pierre Parrend14,15 · Amélie Piton1,2,3,4,16,17 · David A. Koolen9 · Jean‑Louis Mandel1,2,3,4,18

Received: 22 July 2022 / Accepted: 15 November 2022 / Published online: 27 November 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2022

Abstract
Intellectual disability with or without manifestations of autism and/or epilepsy affects 1–2% of the population, and it is
estimated that more than 30–50% of these cases have a single genetic cause. More than 1000 genes and recurrent chromo-
somal abnormalities are involved in these genetic forms of neurodevelopmental disorders, which often remain insufficiently
described in terms of clinical spectrum, associated medical problems, etc., due to their rarity and the often-limited number
of patients’ phenotypes reported. GenIDA is an international online participatory database that aims to better characterise
the clinical manifestations and natural histories of these rare diseases. Clinical information is reported by parents of affected
individuals using a structured questionnaire exploring physical parameters, cognitive and behavioural aspects, the presence
or absence of neurological disorders or problems affecting major physiological functions, as well as autonomy and quality of
life. This strengthens the implication in research of the concerned families. GenIDA aims to construct international cohorts
of significant size of individuals affected by a given condition. As of July 2022, GenIDA counts some 1545 documented
patient records from over 60 nationalities and collaborates with clinicians and researchers around the world who have access
to the anonymized data collected to generate new, medically meaningful information to improve patient care. We present
the GenIDA database here, together with an overview of the possibilities it offers to affected individuals, their families, and
professionals in charge of the management of genetic forms of neurodevelopmental disorders. Finally, case studies of cohorts
will illustrate the usefulness of GenIDA.

Keywords Intellectual disability · Participative study · Rare diseases · Cohorts · Comorbidities

Introduction Psychiatric Association 2013). NDDs are frequently asso-

ciated with each other, but also with other psychiatric or
Neurodevelopmental disorders (NDDs) are developmental neurological manifestations (such as behavioural disor-
impairments in one or more cognitive skills that manifest ders, epilepsy) and other non-neurological comorbidities
early in a child's development, typically before primary (INSERM 2016; Hansen et al. 2018; Des Portes 2020). ID,
school entry. These include intellectual disability (ID), classically characterised by an intelligence quotient (IQ)
autism spectrum disorders (ASD), communication disor- below 70, combines deficits in intellectual functions, such
ders, specific learning disorders (commonly referred to as as reasoning, planning, or abstract thinking, with impair-
“dys” disorders: dyslexia, dyspraxia, etc.), motor disorders ments in adaptive functioning. The latter lead to an inability
(developmental coordination disorder) and attention deficit of the individual to meet developmental and socio-cultural
disorder with or without hyperactivity (ADHD) (American requirements for personal independency and social respon-
sibility, and thus limit functioning in one or more areas of
daily life (communication, social participation, etc.) (Ameri-
* Pauline Burger can Psychiatric Association 2013). ID affects about 1–2%
[email protected] of children and young adults (0.4–0.5% for the most severe
Extended author information available on the last page of the article forms of ID) (Maulik et al. 2011). In 30–40% of cases, ID

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as defined above is accompanied by ASD (Boulanger 2016; Mass Index (BMI) phenotypes, i.e., obesity in the case of a
Bertelli et al. 2020). Similarly, it is estimated that up to one- deletion, and abnormally low BMI in the case of the duplica-
third of people with a diagnosis of ASD have an associated tion (Jacquemont et al. 2011). Finally, ID can be caused by
ID (INSERM 2016; Rosen et al. 2018; Christensen et al. the presence of mutations affecting a single gene. This type
2018). Beyond ASD, people with ID are at risk for somatic of genetic abnormality is cumulatively the most important
and psychiatric comorbidities that have a significant impact cause of ID. Genes involved in such monogenic forms of
on their health, such as epilepsy, motor disorders or dis- ID are far from being all known and the list is still grow-
orders affecting other physiological functions (INSERM ing (Vissers et al. 2016; Turro et al. 2020; Kaplanis et al.
2016). It has been estimated that nearly 40% of people with 2020). The SysID database, recently replaced by SysNDD
ID also present behavioural disorders (Munir et al. 2008). (https://​sysndd.​dbmr.​unibe.​ch/), counted at the time of its
The prevalence of these disorders is 3–5 times higher in last update (November 18, 2021), 1534 "primary ID genes,"
these individuals compared to the general population (Tsa- i.e., genes for which causal monogenic variants have been
kanikos and McCarthy 2013; INSERM 2016; Bertelli et al. identified in a sufficient number of unrelated patients and/or
2020). Common health problems (feeding difficulties, sleep for which there is sufficient clinical information (Kochinke
disorders, vision, or hearing problems) can also have sig- et al. 2016).
nificant consequences for their quality of life. Indeed, while
more frequent in people with ID than in the general popu-
lation, such problems are generally less well detected and Issue
managed because of the difficulties affected individuals have
in expressing themselves in this regard (INSERM 2016; Ba These genes and recurrent chromosomal abnormalities
et al. 2020). It thus appears necessary to better character- correspond to as many distinct rare diseases, which often
ise and understand NDDs and the associated comorbidities, remain insufficiently described in terms of clinical spectrum,
the consequences, and the impact they have on the persons associated medical problems and patients’ natural history
concerned. (evolution of the pathology over the course of a lifetime)
Our understanding of the genetic causes of NDDs and due to their very recent identification.
their diagnosis has improved tremendously over the past dec- In fact, if pathologies recently discovered thanks to the
ade, especially thanks to improved molecular genetic tech- progress of molecular genetics are often poorly known and
niques such as high-throughput sequencing (Next Genera- insufficiently described, this can be also true for diseases
tion Sequencing or NGS) targeting either panels of known that have been identified for several decades. For instance,
ID genes or the whole exome (Whole Exome Sequencing or it required 10 years of diagnostic and phenotypic study
WES), or Comparative Genomic Hybridization (CGH array) of families affected by Fragile X syndrome worldwide
(Cooper et al. 2011; Mefford et al. 2012; Redin et al. 2014; (1991–2001) to establish, from only 5 initial cases, that
Zarrei et al. 2015). These techniques enable the identifica- male carriers of the Fragile X premutation can present with
tion of a causative genetic abnormality in 50–60% of cases a late-onset neurodegenerative disorder, and a further 3 years
of severe ID (Vissers et al. 2016) or around 30% of conclu- were needed to collect data to estimate the age-related pen-
sive molecular diagnosis for mild to severe NDDs (van der etrance of the disease (Rousseau et al. 1991; Hagerman et al.
Sanden et al. 2022). This may be an aneuploidy, e.g., an 2001; Jacquemont et al. 2004). One can also cite the KBG
abnormal number of chromosomes, such as trisomy 21, by syndrome (OMIM #148050), first described in 1975, and
far the most frequent specific cause of ID. This may also for which, only 45 patients were identified until 2006 (Her-
be an abnormality affecting a chromosome segment (dele- rmann et al. 1975; Brancati et al. 2006). In many cases of
tion or duplication of this segment, implying that carriers, specific genetic forms of NDDs, the few clinical publications
instead of having two copies of this segment, have only one devoted to these conditions are based on the observation of
(deletion), or three copies (duplication)). Such chromosomal a small number of patients, often insufficient to define an
rearrangements leading to losses or gains of chromosomal effective management of these pathologies. As these disor-
material are called Copy Number Variant (CNV) and when ders are individually rare or very rare, and very diverse, it
they show frequent recurrence, are at the origin of recog- is extremely difficult for geneticists or other academic spe-
nizable syndromes, such as Prader-Willi syndrome (OMIM cialists who do not regularly follow the affected children
# 176270), which is characterized by hypotonia and feed- and adults to build up consequent cohorts of clinically well-
ing difficulties at birth, followed by early obesity associated characterized patients, and even more so, specific databases.
with hyperphagia (Driscoll et al. 1998). Another striking These limitations in the study of genetic forms of NDDs
example are the recurrent deletion or duplication at chromo- invite the evolution of research, taking into account the rec-
some 16p11.2 initially described as associated with autism ommendations for research issued by the French group of
in 2008 and later shown to also cause mirror extreme Body experts gathered by INSERM (French Institut National de

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GenIDA: an international participatory database to gain knowledge on health issues related… 461

la Santé et de la Recherche Médicale) in the framework of started with a TCF4-cohort (de Winter et al. 2016) and
the collective expertise procedure concerning intellectual focuses currently on 21 genetic forms of ID (WaihonaPedia).
disabilities (INSERM 2016). These recommendations call The Simons Foundation Autism Research Initiative (SFARI)
for future studies in the field of ID to be conducted accord- initially launched the SPARK (Simons Foundation Power-
ing to the quality standards of scientific research, favouring ing Autism Research for Knowledge, sparkforautism.org)
longitudinal studies that allow for the follow-up of cohorts program online targeting individuals living in the U.S. with
of national or even international scope to collect structured a professional diagnosis of ASD, that combined parental
data sets available to researchers. Because of the increase responses to an online questionnaire and professionally con-
in the life expectancy of people with ID with or without ducted phone interviews (Feliciano et al. 2018; SPARK).
ASD, experts also recommend broader coverage of all age The subsequent Simons Searchlight research program (www.​
groups, and the collection in new studies of information on simon​ssear​chlig​ht.​org) further dives into these rare genetic
the evolution of these disorders in adulthood and in older NDDs by collecting detailed, standardised medical histories
people (Ayanouglou 2012; INSERM 2016). These recom- and blood samples and sharing them with many investigators
mendations are in line with practical guidelines issued at (Simons Searchlight). Primarily aimed at English speakers,
the international level to assess and manage intellectual dis- it currently offers study participation in Spanish, French and
ability (Kishore et al. 2019). Dutch. For instance, the neurobehavioural phenotype of 28
To overcome the gap of knowledge about the clinical, individuals with de novo pathogenic/likely pathogenic vari-
cognitive, and behavioural manifestations associated with ants in SLC6A1 was recently refined (Kahen et al. 2021).
each of these numerous genetic disorders, and to favour If the types and frequency of clinical features reported
more inclusive research, it is essential to have cohorts well- (including hypotonia, ID/developmental delay, language
defined in terms of the genetic origin of the ID, age, and sex disorder/speech delay, seizures, ASD, high pain tolerance,
of the affected individuals, built with the participation of and sleep issues) are consistent with previous observations,
those directly concerned, namely, people with ID and their it was also possible to clarify the strengths and weaknesses
relatives/caregivers. Those cohorts should also allow lon- of these patients, and more specifically the specific areas of
gitudinal follow-up of the affected persons to better under- relative strength (socialisation and life skills) and weakness
stand the developmental characteristics and natural history (communication and motor skills) by means of standard-
of these disorders. ised behavioural measures (Vineland Adaptive Behaviour
Such databases and cohorts exist for some relatively com- Scales—VABS, Child Behavior Checklist).
mon conditions, such as Fragile X (FORWARD—Fragile Considering the ever-growing list of genes or recurrent
X Online Registry With Accessible Research Database: CNV involved in ID, and within the existing databases land-
https://​fragi​lex.​org/​our-​resea​rch/​proje​cts/​forwa​rd-​regis​try-​ scape, GenIDA was designed to better characterise the many
datab​ase/; Sherman et al. 2017; Berry-Kravis et al. 2021) genetic forms of ID with or without manifestation of ASD or
or Rett syndrome (https://​www.​retts​yndro​me.​org/​resea​rch/​ epilepsy, corresponding to an equivalent number of rare and
our-​resea​rch/​natur​al-​histo​ry-​study/, Buchanan et al. 2022), distinct disorders, in terms of spectrum of clinical features,
often maintained by researchers and supported by patients’ co-morbidities and progression over time (natural history).
organizations. More recently, numerous patients/families’ It involves parents/caregivers who have the motivation and
groups of varying size have been initiated on social networks the knowledge about the manifestations of the condition.
with support from experts, but only a limited number are GenIDA's participatory approach, as well as the nature of
collecting formalized medical data. Very few recent initia- the variables collected, will be presented through the exam-
tives collect medical and longitudinal data on various dis- ples of 3 case studies initiated from the answers provided by
eases through a participatory online approach. The Human parents/caregivers in the database.
Disease Genes (HDG; https://​www.​human​disea​segen​es.​nl/)
website series represents a systematic international approach
that records detailed information on the clinical phenotype GenIDA
of novel genetic variants in the human genome, including
unpublished clinical information captured through an online The GenIDA1 project (https://​genida.​unist​ra.​fr) is an exam-
questionnaire by clinicians after informed consent (Ding- ple of a novel approach of participatory research targeting
emans et al. 2021). The online patient community Patients- genetic forms of ID, that will bring new insights to their
LikeMe (www.p​ atien​ tslik​ eme.c​ om) has currently a very lim- phenotypic description and natural history delineation.
ited recruitment on genetic forms of ID (PatientsLikeMe). This international participatory database was developed
WaihonaPedia (www.​waiho​naped​ia.​org), a platform allow-
ing the connection and exchanges between affected individ-
uals and their families, caregivers, doctors and therapists, 1
Genetics of Intellectual Disability and Autism spectrum disorders.

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462 P. Burger et al.

and launched online in November 2016, with the aim of The questionnaire
better characterising these rare forms of ID and/or ASD of
genetic origin, via the direct insight of affected individu- The GenIDA questionnaire, designed to be understandable
als and their families that are asked to answer a structured to non-healthcare or research professionals, is currently
questionnaire. GenIDA enables longitudinal studies to be available in 7 languages (French, English, Dutch, Ger-
carried out, to monitor the evolution of cognitive skills man, Spanish, Italian, and Portuguese). Its design ben-
and possible behavioural problems in affected people in eficiated from input, or even translation, from representa-
ecological conditions as the information are reported by tives of some patients’ associations. It currently includes
the parents. 5 free text qualitative questions, 5 numerical questions
The longitudinality of the study lies in the fact there is (weight, height, head circumference, Apgar score, age at
no minimum age requirement or age limit for enrolment of developmental milestones), as well as 36 multiple choice
individuals with these forms of ID in the database. Natural questions (MCQs) with their 92 sub-questions. Each of
history is mainly obtained from the answers by parents of these MCQs also contains a free text field allowing to give
patients of different ages and not by following patients in complementary information (e.g., on clinical manifesta-
GenIDA for a long time. tions, treatment). The MCQs notably investigate cogni-
However, the participating families are encouraged to tive aspects (e.g., diagnosis and degree of ID, spoken
regularly update the data on their affected family member. language competency, etc.), behavioural aspects includ-
Such an update is recommended annually, but because of ing ASD, neurological manifestations (epilepsy, motor
the voluntary nature of participation in this study, it can be defects) and core physiological functions (cardiac, renal,
more or less frequent. Thus, we observe that this data update endocrinal, etc.). The open text questions address percep-
is generally directly concomitant with the occurrence of a tions of manifestations that most affect the health, behav-
new event in the life of the persons concerned (appearance iour, and quality of life of the person with NDD, as well
of a new symptom or comorbidity, adverse effects result- as potential adverse effects of medications administered
ing from medication, etc.). Data update reminders are fre- as part of targeted or symptomatic treatments for comor-
quently posted on GenIDA's Facebook page (www.f​ acebo​ ok.​ bidities. We avoided mandatory responses for the clinical
com/​GenID​Aproj​ect/), and the message is also conveyed by questionnaire by allowing participants to skip questions,
patient organizations (via their own newsletters, their social to answer the questionnaire out of order, and in multiple
networks or at their information meetings). rounds to reduce potential caregiver burden and maximize
The answers are strictly anonymous, and the question- participation. Questions about dysmorphology were inten-
naire can be completed in several rounds. As the aim of tionally omitted.
GenIDA is to better characterise rare forms of ID and/or The questionnaire was designed by GenIDA to be
ASD of genetic origin in terms of associated comorbidi- understandable by lay people and submitted to an interna-
ties and symptomatology, having identified a causal gene, tional advisory board made up of clinicians, researchers, as
or CNV is the only condition for participating in the study. well as concerned parents and representatives of patients’
Such massive data collection right at the source (i.e., the associations. By "lay people", we mean parents/caregivers
affected person and her/his family) will greatly contribute who do not belong to the medical or the scientific research
to accelerate the knowledge about these rare diseases. It world and who are, therefore, not necessarily familiar with
also allows the affected individuals, their families and the the medical lexicon, but who are nevertheless sufficiently
relevant patients' associations to be involved in the construc- aware of the pathology and its comorbidities to be able to
tion of international cohorts of sufficient size from which participate in our study. In more than 91% of cases, one
physicians, researchers and other professionals can extract or both parents of the affected person answered the ques-
new medically significant data to improve the care of people tionnaire. Translations, especially of medical terms and
with the disease. NDD-specific lexical fields, were carefully proofread by
The project was developed in collaboration with RaDiCo a native speaker of the language in comparison with the
(https://​www.​radico.​fr/​en/​accue​il), the French rare disease English version of the questionnaire.
cohort program (RaDiCo—Rare Disease Cohorts) and spe- An online visualization system generates informative
cialists in information security and database management real-time numerical graphs of medical and behavioural
from the ICube laboratory in Strasbourg (P.P.). Potential manifestations and cognitive abilities for each genetic
risks regarding data storage, security, confidentiality, type form of NDD for which there are sufficient participat-
of data requested, or website structure have been considered ing families (these data are updated every 24 h). We have
during the development of this database and are detailed in designed an access control system to fine-tune the access
the validated research protocol of the project (available upon of participating families and association members to
request) submitted to INSERM.

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GenIDA: an international participatory database to gain knowledge on health issues related… 463

disease-specific questionnaires and to specific aggregated or duplication/deletion borders as the latter would be
data analyses, depending on the size of the cohort (Parrend potentially identifying information. The information about
et al. 2018). Additional numerical, textual, and genetic affected individuals undergoes curation and validation steps
data may go through a curation step when needed for a by the GenIDA administrator that occasionally includes, in
specific study. Interested clinicians and researchers, in par- case of inconsistency or error, directly re-contacting caregiv-
ticular those who wish to collaborate on data analysis, can ers by mail for edition.
have access upon request to de-identified statistical data At any time during the completion of the questionnaire,
and textual answers. the participant can download and print for personal use
a PDF file summarizing all the questions with his or her
answers precisely dated. This document constitutes a useful
A database for families compilation of health and quality of life data that can be
attached to the affected person's health record. This docu-
The "participatory" nature of GenIDA comes from the obser- ment can also be used as a memory aid to check whether
vation that parents / caregivers of people with disabilities are the answers given to the GenIDA questionnaire need to be
generally the most knowledgeable about the manifestations updated.
of their disorders. They are indeed the more susceptible to Cohort-specific statistical data based on MCQs are
observe the day-to-day development of their relative and to available directly on the GenIDA website to concerned par-
describe the problems affecting their health and quality of ticipating families when the cohort size is more than 10.
life as stated by (Kishore et al. 2019). Anonymized results from the analysis of cohort-specific
Indeed, families are perfectly able to describe the mani- responses collected can also be shared with relevant stake-
festations of the disease and their effects on the quality of holders at association events (family gatherings, general
life or autonomy of their affected relative, but above all, they assemblies, etc.), or relayed via social networks or patient
can reveal aspects of the pathology that had been underesti- group websites.
mated until then. They are, moreover, particularly motivated
to make progress in knowledge, as shown by the impressive
growth of patient and family associations and groups for rare A database for professionals
diseases, especially on social networks. They are, therefore,
the most eager for answers to their questions about the future The statistical data specific to each cohort, already men-
of the affected person: will she learn to speak, to write?, will tioned above, as well as the free text answers, are also acces-
she be autonomous?, if she suffers epilepsy, will it be treat- sible to medical and paramedical professionals involved in
able?, will it decrease with age?, are there any regression the management and care of this type of genetic disorders
episodes to be feared?, etc. The objective is to collect data (doctors, clinicians, researchers, etc.). To access the de-iden-
corresponding to each dysfunctional gene or chromosomal tified data collected, these professionals must register on
abnormality, and through their analysis, to produce new the GenIDA platform via a separate registration form. This
knowledge that is meaningful for the medical follow-up of registration allows these specialists to express their interest
affected individuals and their families. It is hoped that the in the project and in particular cohorts, and even to become
collected data will allow for an improvement of the manage- more actively involved in the project. Professionals can par-
ment of the care of these pathologies and of information to ticipate in the recruitment of families affected by specific
concerned families. pathogenic genes, syndromes or CNVs. An example of the
To take part in the study, family members (most often joint involvement of an associative partner and clinicians
one of the parents) of a person with a genetic form of ID in recruiting participants is the MED13L cohort, which has
must create a personal space as participant by providing experienced active and steady growth since the first enrol-
a functional email. They must then give consent to par- ment in September 2017 through the combined efforts of the
ticipate in the GenIDA study by producing and regularly French association (Association MED13L Syndrome, www.​
updating medical and quality of life information about their med13​lsynd​rome.​eu) and clinicians from the Lille Univer-
affected relative. Mandatory information is collected about sity Hospital Center, France (Dr. T. Smol, Dr. J. Ghoumid,
the participant (username; email address; password; her/his and Dr. R. Caumes). This cohort counts 44 participants as
relationship with the affected person: parents, grandparents, of July 2022, of which 47% are French families. We have
siblings, referent/guardian). Information collected about the noted an increase in enrolment in this cohort systematically
affected individual during the online registration procedure after each intervention by these clinicians during which they
encompass pseudonym, month and year of birth, sex, and presented results from GenIDA.
name of gene or CNV stated as causal after genetic diagno- Professionals can also participate in the analysis of data
sis without required specification of the exact mutation(s) related to these genes, syndromes or CNVs, and can, in

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Table 1  Major cohorts in GenIDA (as of July 2022)

Cohort Gene/genetic defect (OMIM number) Number of participants
(GenIDA, as of July
2022)

Koolen-de Vries syndrome 17q21.31 deletion (OMIM #610443) 241

or KANSL1 pathogenic variants* (OMIM #612452)
Kleefstra syndrome 9q34.3 deletion (OMIM #610253) 185
or EHMT1 pathogenic variants* (OMIM #607001)
RASopathies PTPN11 (OMIM #176876), BRAF (OMIM #164757) and SOS1 (OMIM 61
#182530) pathogenic variants* mainly
KBG syndrome 16q24.2 / 16q24.2q24.3 deletion (OMIM #148050) 48
or ANKRD11 pathogenic variants* (OMIM #611192)
DDX3X DDX3X pathogenic variants* (OMIM # 300160) 47
MED13L syndrome MED13L pathogenic variants* (OMIM #608771) 45

*(including likely pathogenic variants)

this way, generate new and medically significant knowl- GenIDA nowadays (July 2022)
edge that can translate into improved patient care and
contribute to the drafting of scientific publications, care Registry recruitment was launched in November 2015 for a
management recommendations in the form of guidelines, 1-year beta test, during which time volunteer families were
etc. In particular, the data collected by GenIDA were made included to test the website's functionality and merge after
available to clinicians in charge of writing the PNDS, i.e., consenting their data into the Syndrome Monitor database
the French diagnostic and care management protocols, for (unpublished) developed at Radboud University Medical
Koolen-de Vries, MED13L and Wiedemann-Steiner syn- Centre, Nijmegen, The Netherlands (the latter survey cov-
dromes (all scheduled for publication in the near future). ered 36 of the 46 major questions of the GenIDA sur-
At the international level, data on Kleefstra syndrome are vey). Open recruitment was conducted exclusively on the
currently being reviewed by the team of Dr. T. Kleefstra GenIDA website after November 2016.
(Radboud university medical centre in Nijmegen, The Since then, information about GenIDA has been pre-
Netherlands) for use in the development of Professional sented at several national and international medical con-
clinical guideline for Kleefstra syndrome. ferences and the study has been regularly publicized via
Professionals can also investigate certain aspects of a social media, support groups and at patient family meet-
disease of interest by submitting additional questions to ings in France, and abroad (including mainly the Nether-
the families concerned, or recruit families for clinical stud- lands, the UK, Australia and the US). GenIDA received the
ies and/or research projects. To do so, they must contact active support of many professionals and patients’ associa-
the GenIDA team, which, after consultation and subject tions for the recruitment of patients, and as of July 2022,
to the approval of its scientific advisory committee, will the database has recruited over 1545 caregivers from over
relay the information to the families concerned. The search 60 nationalities who have completed at least 20% of the
for additional information can be done in the form of a questionnaire (past this threshold, the average answer rate
new specific questionnaire developed by the professional is in fact exceeding 80% for over 83% of the participants
in consultation with the GenIDA team and posted on the (Colin et al. under revision)). The recruitment rate is 30
platform, or simply relayed by GenIDA to the families participants on average per month. The database contains
concerned by email (especially if the request involves over 75 000 answers. The main countries of origin of par-
sending medical documents: imaging, etc.). ticipants were France (41.1%), followed by the United
GenIDA satisfies ethical requirements (see “Compli- States (20.8%), the United Kingdom (10.2%), the Nether-
ance with Ethical Standards” paragraph), and the authori- lands (3.7%), Germany (3.6%), and Australia (3.1%). We
sations obtained allow for this type of incidental study have data on 47 specific genes or CNVs for which at least
without seeking specific legal authorisation again as par- 5 patients are documented in the database.
ticipants are asked to give their informed consent before The most numerous cohorts in GenIDA are presented
accessing any questionnaire (general questionnaire, Covid- in Table 1; a variety of new cohorts have also been created
19 questionnaire, etc.).

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GenIDA: an international participatory database to gain knowledge on health issues related… 465

Table 2  Selected cohorts created in GenIDA in the last 2 years, reporting their respective number of participants (as of July 2022)
Cohort Gene/genetic defect (OMIM number) Number of participants
(GenIDA, as of July
2022)

Wiedemann-Steiner syndrome KMT2A pathogenic variants* (OMIM #605130) 29

SETD5 cohort SETD5 pathogenic variants* (OMIM #615761) 28
Phelan-McDermid syndrome 22q13.3 deletion (OMIM #606232) 25
or SHANK3 pathogenic variants* (OMIM #606230)
DYRK1A syndrome DYRK1A pathogenic variants* (OMIM #614104) 24
White Sutton syndrome POGZ pathogenic variants* (OMIM #616364) 20
Coffin-Siris syndrome ARID1A (OMIM #603024), ARID1B (OMIM #614556), ARID2 (OMIM 18
#609539), and SMARCA4 (OMIM #603254) pathogenic variants* mainly

*(including likely pathogenic variants)

over the past year and already have an interesting partici- analysis provided further information on the nature of the
pation rate (Table 2). seizures associated with KdVS, as well as information on
the efficacy and possible adverse effects of the anti-epileptic
treatments used to treat these disorders. With regard to cog-
Case studies nitive abilities, the data show a clear delay in the speech and
reading abilities of KdVS patients, but these tend to improve
Koolen‑de Vries syndrome over time in a majority of them, since according to paren-
tal perception, these abilities seem to be acquired by about
Koolen-de Vries syndrome (KdVS) is caused by the 45% of adolescents. Verbal dyspraxia (reflected by reduced
17q21.31 deletion or by pathogenic variants in KANSL1 understanding of the affected person by family members and
(Koolen et al. 2006, 2012, 2016). The detailed phenotypic strangers) is a major problem, as previously reported (Mor-
features were described from two cohorts totalling 77 gan et al. 2018), which highlights the importance of early
patients (17 individuals with a pathogenic KANSL1 vari- speech and language therapy.
ant) (Zollino et al. 2015; Koolen et al. 2016). Clinical data Comparison of the KdVS data to the overall GenIDA
from 170 individuals with KdVS (probably partly overlap- data shows clinical features that are significantly more fre-
ping with the former cohorts) are now available in the HDG quent in KdVS and that may require extra attention. This
website series (https://​www.​human​disea​segen​es.​nl/​kansl1/​ type of comparison demonstrates an interesting potential for
graph-​and-​chart), but do not include longitudinal informa- GenIDA, because many clinical features in individuals with
tion (Human Disease Genes). The main features of KdVS are NDDs are relatively unspecific, such as hypotonia, or sleep
neonatal hypotonia, developmental delay, intellectual disa- problems. It also confirms previous observations, notably
bility, facial dysmorphism, epilepsy, congenital anomalies of about the gentle nature children / young adults with KdVS,
the heart and urogenital tract and various orthopaedic mani- although behaviour problems including repetitive behav-
festations. The accumulation of information on the natural iour/stereotypes, attention deficit, anxiety, obsessive behav-
history of the condition and the broadening of the spectrum iour, and hyperactivity are also reported. However, those
of clinical elements assessed using the GenIDA platform behavioural problems appear statistically less frequent in
offer the possibility to improve the clinical management of the KdVS cohort compared to Kleefstra syndrome, which
patients by health professionals and caregivers. scores higher for repetitive/stereotypic behaviour, and KBG
In a forthcoming study, the GenIDA data on 237 individu- syndrome, which scores higher for attention deficit, impul-
als with KdVS are reported (Colin et al. under revision). The sivity and aggressiveness.
phenotypic characterisation of the syndrome is consistent It is also worth noting that two incidental studies, con-
with previous reports and there are no significant differences ducted by international collaborators and using the GenIDA
between patients with a 17q21.31 microdeletion and those platform to rapidly reach concerned people with KdVS likely
with a pathogenic variant in KANSL1. Interestingly, the data to participate, have emerged from the study of these data:
analysis also revealed a previously unreported susceptibility
of these patients to respiratory problems (including recur- (i) The first one conducted under the direction of Dr. D.
rent pneumonia, and childhood asthma). The frequency of A. Koolen by the team at Radboud University Medi-
epilepsy reported in GenIDA is consistent with data from cal Centre in Nijmegen, The Netherlands, examines
the medical literature (Myers et al. 2017), but GenIDA data the prevalence, clinical and radiological characteris-

13
466 P. Burger et al.

tics of musculoskeletal problems, notably scoliosis, These examples demonstrate that GenIDA is valuable
in people with KdVS, as GenIDA results indicated in extracting new and medically meaningful information to
the occurrence of scoliosis and abnormal thoracic complement data from clinical studies, which are often per-
kyphosis in more than 27% of these individuals, formed on smaller numbers of patients.
compared with a prevalence of 2–4% in the general
population (Horne et al. 2014). Spinal radiographs, Study of the impact of the 1st Covid‑19 related
MRIs, and corresponding radiological reports for lockdown
scoliosis and additional abnormalities of 54 indi-
viduals with KdVS were reviewed in this interna- Given the particular sanitary situation in 2020, GenIDA
tional retrospective study to assess the occurrence has opened an online investigation into the consequences of
of scoliosis-related clinical conditions and to raise Covid-19-related lockdown on people with genetic NDDs.
awareness for early detection and adequate therapy. For this purpose, a targeted questionnaire was developed
This retrospective cohort study showed that scolio- during the first Covid-19-related lockdown (spring 2020) in
sis is common among the respondents (56%) with a collaboration with Dr. R. Coutelle, child psychiatrist, Uni-
clear increase of the prevalence with age. Systematic versity Hospital, Strasbourg, France, including questions on
screening with coronal and sagittal radiographs of diagnosis, lifestyle and questions regarding behaviour, diet,
the standing spine is, therefore, recommended before and sleep, in the 6-month period before lockdown and dur-
the onset of the growth spurt and at age 18 years ing lockdown. Participants were also asked to evaluate the
(Bouman et al. in preparation). intensity of these problems by severity level and could freely
(ii) Following the analysis of data collected for this comment on the medical and/or quality of life problems they
syndrome in GenIDA, another study focusing on had encountered during this lockdown. This questionnaire
the ophthalmological manifestations of KdVS was was rapidly implemented on the GenIDA platform, and the
conducted by Dr. D. Landau Prat and Dr. D. Sha- call for participation in this study was disseminated to the
lev, MDs (The Goldschleger Eye Institute, Depart- GenIDA community, i.e., participating families and related
ment of Ophthalmology, Sheba Medical Center patient associations and Facebook groups by email and posts
affiliated to the Sackler school of medicine, Tel on social networks. More than 200 questionnaires were com-
Aviv University, Israel). Indeed, while ocular mani- pleted in some 5 weeks (30.04.2020–09.06.2020). After data
festations, including strabismus, hyperopia, and curation, a total of 199 files of participants (144 children and
ptosis, have been reported in KdVS, detailed data 45 adults) with NDDs (ID: 79.4%, and/or ASD: 21.6%) of
remained restricted. Families of individuals with various genetic origins, from some 15 different nationali-
KdVS already included in GenIDA were recontacted ties mainly from Europe and North America, were included
for inclusion in this study, which aimed to deepen (Coutelle et al. 2022). The apparently small overlap between
insight on known ophthalmological manifestations ID and ASD is due to a bias, namely, that once a diagnosis
(occurrence and frequency of ocular and oculofa- has been made (ID or ASD), formal investigations are usu-
cial malformations) while uncovering novel ocular ally stopped outside of strict research protocols (Myers et al.
associations. Participants were asked to answer to a 2020).
specific questionnaire regarding ocular and adnexal The average duration of lockdown at the time of the sur-
issues and to transmit ophthalmological data, such vey was 57 days. No difference in the frequency and inten-
as clinical visits reports and test results, as well as sity of eating and sleep disorders was evidenced before and
clinical photos of their ocular area to examine eyelid during lockdown. A decrease in sociability scores with
abnormalities. This specific questionnaire distrib- both familiar and unfamiliar children and with adults dur-
uted by GenIDA to all participants in the cohort was ing lockdown was observed. For persons with behavioural
available in English and French from August 2021 problems at both periods, relatives reported an increase in
to January 2022: a total of 67 families, one-third of aggressivity, self-aggressivity, depressiveness, stereotyp-
which were from Europe, took part in this study. The ies, and restricted interests during lockdown, all of which
study's findings indicated that KdVS is associated might be interpreted as consequences of a lack of stimu-
with various ophthalmic findings, such as amblyopia, lation or a reaction to unexpected changes in daily habits
strabismus, refractive errors, and upper eyelid pto- (including notably therapy and/or education cessation during
sis. Retinal abnormalities and nasolacrimal disorders lockdown).
were described for the first time in KdVS (Shalev These results show the interest of GenIDA for lon-
et al. submitted). Thorough ophthalmic assessment gitudinal follow-up of people with NDDs of genetic ori-
is, therefore, recommended for all KdVS individuals. gin, and demonstrate the plasticity of the database, which
allows for the rapid implementation of new specific online

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GenIDA: an international participatory database to gain knowledge on health issues related… 467

questionnaires and the ability to quickly mobilize a large their investment of time in answering the questionnaire (so
number of participants for a new study. did the announcement of the preparation of French guide-
lines for WSS as well).
Neurocognitive and neurobehavioural
characterization of the DYRK1A and Wiedemann–
Steiner syndromes GenIDA’s limitations

DYRK1A and Wiedemann–Steiner (WSS) syndromes The GenIDA questionnaire may appear rather lengthy and
are among the most common monogenic forms of NDD, requires that caregivers, when a patient is already a few years
caused by pathogenic variants in the DYRK1A and KMT2A old, go back to his or her medical record to report accurate
genes, respectively (McRae et al. 2017), and are associ- information. This is tedious to some caregivers and may
ated with both ID and ASD. While the clinical phenotypes account for low answer rate by some participants. They are,
of these two syndromes have been widely described (van therefore, regularly reminded that it is possible to fill in the
Bon et al. 2016; Sheppard et al. 2021), their behavioural questionnaire in several rounds without this affecting the
and neurocognitive profiles have not been systematically interest of their participation in the study, since each answer
assessed using standardised tools. To address this, we com- is recorded and dated precisely, and that they are asked to
bine a clinical study carried out using adapted and validated specify the age of the patient corresponding to each answer
tools (DYRK1A syndrome: n = 14 and WSS: n = 21), and given. On the other hand, there is a lack of ergonomics in the
information reported by participating families in GenIDA software tool, which is currently being revised according to
(DYRK1A syndrome: n = 20 and WSS: n = 20) to character- the feedback received from GenIDA’s users.
ize patients' adaptive behavioural profiles, autistic features, It is also necessary to consider the access to a personal
ADHD symptomatology, anxiety disorders, maladaptive computer (or tablet) not always democratized according to
behaviours, and sensory disorders. Significantly higher, but the countries or social categories, and the capacity of each
also more heterogeneous, adaptive functioning was reported one to use or not such an electronic device more or less
in the WSS group compared to the DYRK1A syndrome easily. We noted that a certain number of older caregivers
group from the clinical study. A diagnosis of ASD was (often grandparents of patients) required more assistance
established for 57% of individuals with DYRK1A syndrome to access the questionnaire or to download the summary
compared to only 24% of those with WSS. Severe communi- of their answers in PDF format than those of a more recent
cation and speech impairments are observed in people with generation. The GenIDA project also faces the limitations
DYRK1A syndrome, which is confirmed by the GenIDA inherent in questionnaire studies, including recall bias, miss-
data, which also show higher comprehension skills than lan- ing answers, and variable personal interpretation of ques-
guage and communication skills. Their use of various means tions by respondents.
of alternative communication—gestures, sounds, pictures, Two major biases of GenIDA from a purely genetic per-
sign language—was reported in both the clinical study and spective are (1) genes with multiple associated syndromes
in GenIDA. The clinical exploration of behavioural pheno- (e.g., depending on the type of mutation), (2) inherited
types revealed the importance of anxiety symptomatology genetic forms of NDDs in which the parents of the individ-
and signs of ADHD in patients with WSS, also reported in ual concerned are themselves more or less severely affected
GenIDA. This study, describing the behavioural and neuro- and will, therefore, tend to respond less. GenIDA is, there-
cognitive profiles of individuals with WSS and DYRK1A fore, more suitable for genetic forms of NDDs occurring de
syndrome, highlighted some important specificities to be novo, or for recessive ones.
addressed in patients' management (Durand et al. 2022).
This project demonstrates the opportunity that GenIDA
offers to study specific aspects of smaller cohorts in depth Conclusions
and even to compare NDDs with each other. The results also
demonstrate the complementarity and the consistency of ret- The participatory and empowering approach on which
rospective clinical studies, and the data collected through GenIDA relies is original and innovative given the
parent/caregiver testimonies in GenIDA. direct involvement of families, who become actors in the
It is also important to note that the announcement of research. GenIDA allows, in the context of rare or even
the initiation of this study to the respective patients’ asso- very rare diseases, such as genetic forms of ID, to effi-
ciations, allowed the recruitment of new participants to ciently build well-defined cohorts of persons with a given
GenIDA. Indeed, the prospect of having their data analysed condition, of sufficient size to obtain quality data to better
by clinicians, in a relatively short time frame, quickly mobi- understand the developmental characteristics of these dis-
lized new participants who saw a concrete perspective to orders. Because of its properties and the variables studied,

13
468 P. Burger et al.

GenIDA is particularly well suited to longitudinal studies Author contributions Conceptualization: PB, J-LM; Design and devel-
that will help to clarify the natural history of these rare opment of database and confidentiality model: TM, PP; Formal analy-
sis and investigation: PB, FC, AS, NC, RC, BD, AB, DLP, TK, AP,
genetic diseases. DAK, J-LM; Writing—original draft preparation: PB, J-LM; Writing—
Our experience with Koolen–deVries syndrome but also review and editing: FC, AS, TM, NC, RC, BD, AB, DLP, TK, PP, AP,
with smaller cohorts (DYRK1A and Wiedeman–Steiner syn- DAK; Funding acquisition: PB, FC, AS, J-LM; Project administration:
dromes) shows the power and potential of a participative PB, FC, AS, J-LM; Supervision: J-LM.
approach and the willingness of caregivers to participate in Data availability statement Data specific to a patient cohort in GenIDA
studies dealing with rare diseases affecting their relative as are accessible in processed form via the visualization tab (https://​
they are truly "experts" on the disorder. By reporting their genida.​unist​ra.​fr/​visua​lizat​ions/), item by item, on the website to any
observations anonymously, they provide researchers with person registered in GenIDA in the said cohort (https://​genida.​unist​ra.​
fr/​regis​ter/) as soon as the threshold of 10 completed files for the said
valuable data, which can after statistical analysis bring use- condition is reached (defined for statistical analysis).
ful new knowledge in rare genetic NDDs, and may help to
identify new aspects that have been overlooked by clinicians Declarations
in previous publications. GenIDA syndrome-specific results
are so far consistent with previous data published in the Conflict of interest The authors have no relevant financial or non-fi-
nancial interests to disclose.
medical literature, while providing greater phenotypic rich-
ness regarding the conditions studied, for instance concern- Ethical approval GenIDA satisfies all ethical requirements: the
ing previously under- or over-estimated susceptibility to cer- research is carried out in accordance with the provisions of the French
tain comorbidities or informing on perceived efficacy and/ Data Protection Act (French law of 6 January 1978, amended by the
law of 6 August 2004 on the protection of individuals regarding the
or adverse effects of specific treatments. To date, GenIDA processing of personal data), and complies with the General Data Pro-
has documented some 35 genes/CNVs (cohort size ≥ 10) tection Regulation 2016/679 (GDPR). The study has been declared to
responsible for ID, but our goal is to increase the number of the French Commission on Information Technology and Liberties on
participating families internationally to open new fields of 27/11/2015, number 1907912v0. It has been reviewed and approved by
the Ethics Evaluation Committee of INSERM—Institut National de la
investigation of other genes and to improve the knowledge Santé Et de la Recherche Médicale—(IORG0003254, FWA00005831),
of genetic NDDs, providing new and useful data for affected the Institutional Review Board (IRB00003888) of the French Insti-
individuals and families concerned, as well as for profession- tute of Medical Research and Health on 15/11/2016, number 16–338,
als involved in the care of these patients. Interoperability and on 04/09/2019, number 16–338 bis. Participants are asked to
read the information note and to give their informed consent before
with existing registries dedicated to rare diseases, and in accessing any questionnaire on the GenIDA website (general question-
particular to specific forms of ID, is planned to be imple- naire, Covid-19 related lockdown questionnaire, etc.). This consent
mented in the near future and should eventually allow the form details the terms and conditions of participation in the GenIDA
development of collaborative projects on a European scale, research. It specifies that participation is free and that the agreement
to participate can be withdrawn at any time, without justification of
combining "participatory" data with clinical data. any kind, simply by logging back into one's account on the GenIDA
website. Hence, informed consent is obtained from all participants to
Supplementary Information The online version contains supplemen- the GenIDA studies, i.e., either the subject him/herself or his/her rela-
tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00702-0​ 22-0​ 2569-3. tive responding to the study on behalf of the person with ID (parent or
legal guardian(s)).
Acknowledgements The authors wish to thank the Institute for
Advanced Studies of the University of Strasbourg (USIAS), the Univer-
sity of Strasbourg Foundation (Roche Fund for Personalized Medicine),
the Fondation Jérôme Lejeune and the National Research Network
“Groupement d’Intérêt Scientifique Autisme et Troubles du Neuro- References
Développement” (GIS Autisme et TND) for their financial support.
The GenIDA project is supported by the French RaDiCo (Rare Disease American Psychiatric Association (2013) DSM-5: diagnostic and sta-
Cohorts) research program for national and European cohorts of rare tistical manual of mental disorders, 5th edn. American Psychiatric
disease patients. This work is generated within the European Reference Association, Washington DC
Network for Intellectual disability, TeleHealth, Autism and Congenital Ayanouglou F (2012) Évolution de personnes adultes avec autisme
Anomalies (ITHACA). Finally, the authors would like to express their et déficience intellectuelle : étude rétrospective. Thèse pour
warmest thanks to all the GenIDA participants and patients’ associa- l’obtention du grade de Docteur en Psychologie, Université Paul
tions and Facebook groups that support us, and notably the Koolen-de Valéry - Montpellier III, https://​tel.​archi​ves-​ouver​tes.​fr/​tel-​00817​
Vries Syndrome Foundation, the Kool Kid Alliance, Koolen-de Vries 991/​docum​ent
France, Kleefstra syndrome Community, Kleefstra Syndrome France, Ba M, Daniluk AM, Salamun J et al (2020) Top 5 des problèmes soma-
Association KBG France, KBG Foundation, Xtraordinaire – Commis- tiques chez les personnes en situation de handicap mental avec
sion DDX3X, DDX3X Foundation, Association MED13L syndrome, troubles du comportement. Rev Med Suisse 16:1796–1800
MED13L Foundation, White-Sutton France, DYRK1A Syndrome Berry-Kravis E, Filipink RA, Frye RE et al (2021) Seizures in frag-
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tion/Deletion/Duplication Patient And Family Support Group and 3389/​fped.​2021.​736255
Coffin-Siris France.

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Authors and Affiliations

Pauline Burger1,2,3,4 · Florent Colin1,2,3,4,5 · Axelle Strehle1,2,3,4 · Timothée Mazzucotelli1,2,3,4 · Nicole Collot1,2,3,4 ·
Romain Coutelle6,7 · Benjamin Durand8 · Arianne Bouman9 · Daphna Landau Prat10,11,12 · Tjitske Kleefstra9,13 ·
Pierre Parrend14,15 · Amélie Piton1,2,3,4,16,17 · David A. Koolen9 · Jean‑Louis Mandel1,2,3,4,18

1 8
Department of Neurogenetics and Translational Medicine, Service de Génétique Médicale, Institut de Génétique
Institute of Genetics and Molecular and Cellular Biology Médicale d’Alsace, Hôpitaux Universitaires de Strasbourg,
(IGBMC), Illkirch, France Strasbourg, France
2 9
Institut National de la Santé et de la Recherche Médicale, U Department of Human Genetics, Donders Institute for Brain,
1258, Illkirch, France Cognition and Behaviour, Radboud University Medical
3 Center, Nijmegen, The Netherlands
Centre National de la Recherche Scientifique, UMR 7104,
10
Illkirch, France Division of Ophthalmology, The Goldschleger Eye Institute,
4 Sheba Medical Center, Tel Hashomer, Israel
Université de Strasbourg, Strasbourg, France
11
5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Present Address: INSERM UMR S1109, Tumor
Israel
Biomechanics Lab, Fédération de Médecine Translationnelle
12
de Strasbourg (FMTS), University of Strasbourg, Strasbourg, The Sheba Talpiot Medical Leadership Program,
France Tel Hashomer, Israel
6 13
Service de Psychiatrie de l’enfant et de l’adolescent, Centre of Excellence for Neuropsychiatry, Vincent Van Gogh
Hôpitaux Universitaires de Strasbourg, Strasbourg, France Institute for Psychiatry, Venray, The Netherlands
7
INSERM U 1114, Clinique Psychiatrique, Strasbourg, France

13
GenIDA: an international participatory database to gain knowledge on health issues related… 471

14 17
ICube Laboratory (Laboratoire Des Sciences de l’ingénieur, Institut Universitaire de France, Paris, France
de l’informatique et de l’imagerie), UMR 7357, Université de 18
University of Strasgourg Institute for Advanced Studies
Strasbourg, CNRS, Strasbourg, France
(USIAS), University of Strasbourg, Strasbourg, France
15
EPITA, Strasbourg, France
16
Laboratoire de Diagnostic Génétique, IGMA, Hôpitaux
Universitaire de Strasbourg, Strasbourg, France

13