Background Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the ZNF148 gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.
Methods As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.
Results The core clinical phenotype is characterised by developmental delay particularly in the domain of speech development, postnatal growth retardation, microcephaly and facial dysmorphism. Corpus callosum abnormalities appear less frequently than suggested by previous observations. The identified mutations concerned nonsense or frameshift variants that were mainly located in the last exon of the ZNF148 gene. Heterozygous deletion including the entire ZNF148 gene was found in only one case. Most mutations occurred de novo, but were inherited from an affected parent in two families.
Conclusion The GDACCF syndrome is clinically diverse, and a genotype-first approach, that is, exome sequencing is recommended for establishing a genetic diagnosis rather than a phenotype-first approach. However, the syndrome may be suspected based on some recurrent, recognisable features. Corpus callosum anomalies were not as constant as previously suggested, we therefore recommend to replace the term ‘GDACCF syndrome’ with ‘ZNF148-related neurodevelopmental disorder’.
- Genetic Counselling
- Behaviour and Behaviour Mechanisms
Data availability statement
Data are available upon reasonable request. Not applicable.
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Correction notice This article has been corrected since it was published Online First. The name of one author has been amended to include the middle name's initial.
Contributors KS and SJCS designed and supervised the study and coordinated the international collaboration. KS analysed the data and wrote the manuscript with input from all authors, KS acting as guarantor. GM, CML, BC, DG, FR, DM, A-SD-P, WP, FPV, RHG, KEA, JK, JCG, EG, BWvB, HGB, OC, UG, MK. MMK, AKB, AMC-G, ACM, SR, LBS; PF, IA, AS-F, VMcN, SAA, HB, GB did the patient clinical work-up and provided phenotypic data. AV, RL, EWK, CK, SJ, KvG, TR, RP, TBH, DB, DC, EMCS and BP analysed the whole exome sequencing data and provided genotypic data. Authors’ contribution also included consultation, correction and proofreading the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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