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

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

doi:10.1371/journal.pone.0208324

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.

Highlights

Intellectual disability (ID) is an early-onset neurodevelopmental disorder affecting 1% of the general population [1]
While research elucidating chromosomal aberrations, copy number variations (CNVs), autosomal dominant, and X-linked variants as causes for ID has been well established, it was not until recently that studies focusing on autosomal recessive forms of ID (ARID) have gained attention [6,8]
We have identified causative variants in 10 out of 21 Turkish families with nonsyndromic ARID

Summary

Introduction

Intellectual disability (ID) is an early-onset neurodevelopmental disorder affecting 1% of the general population [1]. ID is characterized by a significant impairment in cognitive ability and adaptive behavior affecting memory, language, problem solving, and visual comprehension, which can lead to impairments in activities of daily living such as self-care and interpersonal communication. Environmental factors, such as teratogens, infections, malnutrition, and neurological trauma as well as genetic conditions can cause ID. To reveal the causative variants in ARID, we performed Whole Exome Sequencing (WES) in 21 families affected by non-syndromic ID; these families either had multiple affected family members or pedigrees suggestive of consanguinity

Methods

Results

Conclusion