Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome

Dyment D. A., O'Donnell-Luria A., Agrawal P. B., Coban Akdemir Z., Aleck K. A., Antaki D., ...Daha Fazla

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, cilt.185, sa.1, ss.119-133, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 185 Sayı: 1
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1002/ajmg.a.61926
  • Dergi Adı: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, BIOSIS, CAB Abstracts, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.119-133
  • Anahtar Kelimeler: Dubowitz syndrome, exome sequencing, genetic heterogeneity, genome sequencing, microarray, LOSS-OF-FUNCTION, INTELLECTUAL DISABILITY, MUTATIONS, ANEMIA, NSUN2, FRAMESHIFT, PHENOTYPE, ANOMALIES, PLATFORM, PATIENT
  • Marmara Üniversitesi Adresli: Evet

Özet

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.