Comparative deletion mapping at 1p31.3-p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability

Abstract

BackgroundWhile chromosome 1 is the largest chromosome in the human genome, less than two dozen cases of interstitial microdeletions in the short arm have been documented. More than half of the 1p microdeletion cases were reported in the pre-microarray era and as a result, the proximal and distal boundaries containing the exact number of genes involved in the microdeletions have not been clearly defined.ResultsWe revisited a previous case of a 10-year old female patient with a 1p32.1p32.3 microdeletion displaying syndromic intellectual disability. We performed microarray analysis as well as qPCR to define the proximal and distal deletion breakpoints and revised the karyotype from 1p32.1p32.3 to 1p31.3p32.2. The deleted chromosomal region contains at least 35 genes including NFIA. Comparative deletion mapping shows that this region can be dissected into five chromosomal segments containing at least six candidate genes (DAB1, HOOK1, NFIA, DOCK7, DNAJC6, and PDE4B) most likely responsible for syndromic intellectual disability, which was corroborated by their reduced transcript levels in RT-qPCR. Importantly, one patient with an intragenic microdeletion within NFIA and an additional patient with a balanced translocation disrupting NFIA display intellectual disability coupled with macrocephaly.ConclusionWe propose NFIA is responsible for intellectual disability coupled with macrocephaly, and microdeletions at 1p31.3p32.2 constitute a contiguous gene syndrome with several genes contributing to syndromic intellectual disability.

Loss‐of‐function variants in NFIA provide further support that NFIA is a critical gene in 1p32‐p31 deletion syndrome: A four patient series

“…Deletions in the 1p31.3 locus involving the NFIA gene have been reported several times in the literature (Campbell, Wang, & Hunter, ; Chen et al, ; Ji, Salamon, & Quintero‐Rivera, ; Koehler et al, ; Labonne et al, ; Lu et al, ). Recently, Labonne et al () used comparative deletion mapping and identified NFIA as a gene in the minimal region of overlap among reported 1p31.3‐p32.2 microdeletions.…”

“…Deletions in the 1p31.3 locus involving the NFIA gene have been reported several times in the literature (Campbell, Wang, & Hunter, ; Chen et al, ; Ji, Salamon, & Quintero‐Rivera, ; Koehler et al, ; Labonne et al, ; Lu et al, ). Recently, Labonne et al () used comparative deletion mapping and identified NFIA as a gene in the minimal region of overlap among reported 1p31.3‐p32.2 microdeletions. By comparing the phenotype of five individuals with NFIA alterations (including three microdeletions and two translocations that disrupted NFIA ) and supporting animal studies, Lu et al () suggested that NFIA gene haploinsufficiency was responsible for a novel syndrome that included central nervous syndrome malformations as well as ureteral and renal defects.…”

“…Common features of this microdeletion include agenesis/hypoplasia of the corpus callosum, mental retardation, seizures, ventriculomegaly, Chiari I malformation, hypotonia, macrocephaly, and dysmorphic features including broad forehead, low‐set ears, and small chin (see, Table S1 in supplementary materials) (Koehler et al, ; Lu et al, ). Recently, Labonne et al () used comparative deletion mapping of all reported cases of 1p31.3p32.2 deletions, identifying NFIA as a gene in the minimal region of overlap and the gene likely responsible for intellectual disability and macrocephaly seen in individuals with this microdeletion. NFIA gene disruptions resulting from balanced translocations and intragenic deletions have also been reported with features consistent with the 1p32‐p31 deletion syndrome (Bayat, Kirchhoff, Madsen, Roos, & Kreiborg, ; Coci et al, ; Lu et al, ; Mikhail et al, ; Nyboe, Kreiborg, Kirchhoff, & Hove, ; Rao et al, ).…”

Chromosome 1p31.1p31.3 Deletion in a Patient with Craniosynostosis, Central Nervous System and Renal Malformation: Case Report and Review of the Literature

“…Asterisks represent autosomal control probes. Sivasankaran et al, 1997;Zinner and Batanian 2003;Shaw-Smith et al, 2004;Gillberg and FitzPatrick, 2010;Chen et al, 2011;Ji et al, 2014;Tassano et al, 2015;Labonne et al, 2016]. There are also 5 cases with significantly smaller deletions, all presenting with a milder phenotype ( fig.…”

“…With the exception of the 1p36 syndrome (MIM 607872), interstitial deletions affecting the short arm of chromosome 1 are rare, with only ∼ 20 cases reported in the literature [Labonne et al, 2016]. Three of these are deletions encompassing the whole 1p31.1p31.3 region ( fig.…”