Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability

Megan McSherry, Katherine E. Masih, Nursel H. Elcioglu, Pelin Celik, Ozge Balci, Filiz Basak Cengiz, Daniella Nunez, Claire J. Sineni, Serhat Seyhan, Defne Kocaoglu, Shengru Guo, Duygu Duman, Guney Bademci, Mustafa Tekin

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Abstract

The etiology of intellectual disability (ID) is heterogeneous including a variety of genetic and environmental causes. Historically, most research has not focused on autosomal recessive ID (ARID), which is a significant cause of ID, particularly in areas where parental consanguinity is common. Identification of genetic causes allows for precision diagnosis and improved genetic counseling. We performed whole exome sequencing to 21 Turkish families, seven multiplex and 14 simplex, with nonsyndromic ID. Based on the presence of multiple affected siblings born to unaffected parents and/or shared ancestry, we consider all families as ARID. We revealed the underlying causative variants in seven families in MCPH1 (c.427dupA, p.T143Nfs*5), WDR62 (c.3406C>T, p.R1136*), ASPM (c.5219_5225delGAGGATA, p.R1740Tfs*7), RARS (c.1588A>G, p.T530A), CC2D1A (c.811delG, p.A271Pfs*30), TUSC3 (c.793C>T, p.Q265*) and ZNF335 (c.808C>T, p.R270C and c.3715C>A, p. Q1239K) previously linked with ARID. Besides ARID genes, in one family, affected male siblings were hemizygous for PQBP1 (c.459_462delAGAG, p.R153Sfs*41) and in one family the proband was female and heterozygous for X-chromosomal SLC9A6 (c.1631+1G>A) variant. Each of these variants, except for those in MCPH1 and PQBP1, have not been previously published. Additionally in one family, two affected children were homozygous for the c.377G>A (p.W126*) variant in the FAM183A, a gene not previously associated with ARID. No causative variants were found in the remaining 11 families. A wide variety of variants explain half of families with ARID. FAM183A is a promising novel candidate gene for ARID.

Original languageEnglish (US)
Article numbere0208324
JournalPLoS One
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2018

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Genetic Heterogeneity
Genetic Association Studies
Intellectual Disability
Genes
genes
counseling
recessive genes
Recessive Genes
etiology
ancestry
Siblings
Exome
Consanguinity
Genetic Counseling
Parents
Research

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Identification of candidate gene FAM183A and novel pathogenic variants in known genes : High genetic heterogeneity for autosomal recessive intellectual disability. / McSherry, Megan; Masih, Katherine E.; Elcioglu, Nursel H.; Celik, Pelin; Balci, Ozge; Cengiz, Filiz Basak; Nunez, Daniella; Sineni, Claire J.; Seyhan, Serhat; Kocaoglu, Defne; Guo, Shengru; Duman, Duygu; Bademci, Guney; Tekin, Mustafa.

In: PLoS One, Vol. 13, No. 11, e0208324, 01.11.2018.

Research output: Contribution to journalArticle

McSherry, M, Masih, KE, Elcioglu, NH, Celik, P, Balci, O, Cengiz, FB, Nunez, D, Sineni, CJ, Seyhan, S, Kocaoglu, D, Guo, S, Duman, D, Bademci, G & Tekin, M 2018, 'Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability', PLoS One, vol. 13, no. 11, e0208324. https://doi.org/10.1371/journal.pone.0208324
McSherry, Megan ; Masih, Katherine E. ; Elcioglu, Nursel H. ; Celik, Pelin ; Balci, Ozge ; Cengiz, Filiz Basak ; Nunez, Daniella ; Sineni, Claire J. ; Seyhan, Serhat ; Kocaoglu, Defne ; Guo, Shengru ; Duman, Duygu ; Bademci, Guney ; Tekin, Mustafa. / Identification of candidate gene FAM183A and novel pathogenic variants in known genes : High genetic heterogeneity for autosomal recessive intellectual disability. In: PLoS One. 2018 ; Vol. 13, No. 11.
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AU - Cengiz, Filiz Basak

AU - Nunez, Daniella

AU - Sineni, Claire J.

AU - Seyhan, Serhat

AU - Kocaoglu, Defne

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