In:
Journal of Medical Genetics, BMJ, Vol. 57, No. 7 ( 2020-07), p. 466-474
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0022-2593
,
1468-6244
DOI:
10.1136/jmedgenet-2019-106425
Language:
English
Publisher:
BMJ
Publication Date:
2020
detail.hit.zdb_id:
2009590-9
SSG:
12
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