Abstract

Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly and has been associated with higher risk of neurodevelopmental and behavioural problems indicating potential shared genetic factors between CL/P and neurodevelopmental disorders. In this study, we aimed to determine the prevalence of neurodevelopmental copy number variants (CNV) in children with CL/P and their link to early developmental and behavioural problems. Using data from the Cleft Collective, the largest UK-based national cohort study of children with CL/P, we determined the rates of neurodevelopmental CNVs in children with CL/P comparing them to the general population, explored differences by cleft type and investigated risk of developmental delays and behavioural problems among those with CL/P and neurodevelopmental CNVs. Children with CL/P had a higher prevalence of neurodevelopmental CNVs than participants in four population-based samples (3.7% vs 2.3% in the Avon Longitudinal Study of Parents and Children (ALSPAC), 2.0% in Born in Bradford (BiB), 2.3% in Millenium Cohort Study (MCS), 1.7% in UK Biobank, ORs(95%CIs): ALSPAC= 1.56(1.18-2.06), BiB= 1.84(1.37-2.45), MCS= 1.59(1.19-2.11), UK Biobank= 2.15(1.68–2.71). Children with cleft palate only were 3 times more likely to have a neurodevelopmental CNV (95%CIs1.50-6.59, p=0.03) than children with cleft lip only. Furthermore, children with CL/P and neurodevelopmental CNVs were more likely to experience early developmental delays and behavioural problems by age 5 compared to children with CL/P and without neurodevelopmental CNVs. These findings highlight that genetic testing ascertaining the presence of neurodevelopmental CNVs might be helpful in early identification of developmental needs in children with CL/P.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was funded in whole by the Medical Research Council MRC (MR/W020297/1). For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) public copyright license to any Author Accepted Manuscript (AAM) version arising from this submission. RB, AR, SL and ES are employed in the MRC Integrative Epidemiology Unit (IEU) (MC_UU_00032/1 - Programme 1: Mendelian Randomization). SJL received support for this study from an MRC project grant (MR/T002093/1). CD is funded by the Wolfson Centre for Young People Mental Health, established with support from the Wolfson Foundation. MJO is funded by the Medical Research Council (MR/L010305/1 and programme grant MR/P005748/1). KK is funded by the Mental Health Mission. ER is funded by the UKRI MRC Programme Grant (MR/Y004094/1) and UKRI Future Leaders Fellowship Grant (MR/Y033922/1). MBMvdB is funded by the Medical Research Council (MR/V004905/1RE). MBMvdB also acknowledges funding from the Tackling Multimorbidity at Scale Strategic Priorities Fund programme (MR/W014416/1) delivered by the Medical Research Council and the National Institute for Health Research in partnership with the Economic and Social Research Council and in collaboration with the Engineering and Physical Sciences Research Council. This publication involves data derived from independent research funded by The Scar Free Foundation; additional funding was provided by The Underwood Trust and the Vocational Training Charitable Trust (VTCT) (REC approval 13/SW/0064). We are grateful to the families who participated in the study, the UK NHS cleft teams, and The Cleft Collective team, who helped facilitate the study. The views expressed in this publication are those of the author(s) and not necessarily those of The Scar Free Foundation, The Underwood Trust, the Vocational Training Charitable Trust or The Cleft Collective Cohort Study team. For the data used from the Born in Bradford cohort study we want to acknowledge that Born in Bradford is only possible because of the enthusiasm and commitment of the children and parents in BiB. We are grateful to all the participants, health professionals, schools, and researchers who have made Born in Bradford happen. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol http://www.bristol.ac.uk/acrc/.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Cleft Collective Cohort Studies received ethical approval from the South-West Central Bristol NRES Ethics Committee (REC 13/SW/0064). This project was approved by the Cleft Collective project management group (CC048-ES).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available from the Cleft Collective upon reasonable request.

AbbreviationsALSPACAvon Longitudinal Study of Parents and ChildrenASQ:SE-2Ages and Stages Questionnaire - Social Emotional 2ASQ-3Ages and Stages Questionnaire 3BiBBorn in BradfordCIConfidence IntervalCL/PCleft Lip and/or PalateCNVCopy Number VariantGCSEGeneral Certificate of Secondary EducationGSAGlobal Screening ArraykbKilobaseMCSMillenium Cohort StudyND CNVNeurodevelopmental Copy Number VariantQCQuality ControlSDQStrengths and Difficulties questionnaire