Purpose Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan–Fryns syndrome explain no more than 20% of subjects.
Methods To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.
Results We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.
Conclusion We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10−4) and genes regulated by the fragile X mental retardation protein (p=3×10−8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
- marfanoid habitus
- intellectual deficiency
- exome sequencing
- chromatin remodeling
- de novo variants
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MC, YD, RAB, J-BR, BJO and LF contributed equally.
Contributors LF and JBR designed the study. MC, FD, CC, JSO, TJ, RO, DL, CP, AB, JFD performed the genetics experiments. FL, PK, JT, PC, GCB, MA, VC, LD, FTMT, CP, AV, ALB analysed the genetic results. YD performed the bioinformatics experiments. RAB and BOR performed the statistical experiments. SM, DL, MAD, CG, FMP, JVG, AM, SL, VCD, GB, MH, FP, BL, SO, PSK, GL, DG, PC, DMC, AJ, LP, AP, ES, KA, IM, CC, SJ, EL, FD, AG, MDF, CM, DH, NJM, AM, SEC, NM, FH, PA, NH, CB, GJ recruited and evaluated the study subjects. EG and CB were in charge of the administrative follow-up of the study. LF, CTR, JBR, BOR supervised the study. LF, BOR, MC, YD, and RAB wrote the manuscript. All authors revised the manuscript.
Funding This work was funded by the French Ministry of Health (PHRC national 2008/2008-A00515-50), the Regional Council of Burgundy / Dijon University hospital (PARI 2012) and the European Union through the PO FEDER-FSE Bourgogne 2014/2020. B.J.O. is a Klingenstein-Simons (Esther A. & Joseph Klingenstein Fund, Simons Foundation) and Sloan Research (Alfred P. Sloan Foundation) Fellow in Neurosciences.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository.