A de novo 1q22q23.1 Interstitial Microdeletion in a Girl with Intellectual Disability and Multiple Congenital Anomalies Including Congenital Heart Defect

Abstract

Many studies have shown that molecular karyotyping is an effective diagnostic tool in individuals with developmental delay/intellectual disability. We report on a de novo interstitial 1q22q23.1 microdeletion, 1.6 Mb in size, detected in a patient with short stature, microcephaly, hypoplastic corpus callosum, cleft palate, minor facial anomalies, congenital heart defect, camptodactyly of the 4-5th fingers, and intellectual disability. Chromosomal microarray analysis revealed a 1.6-Mb deletion in the 1q22q23.1 region, arr[GRCh37] 1q22q23.1(155630752_157193893)×1. Real-time PCR analysis confirmed its de novo origin. The deleted region encompasses 50 protein-coding genes, including the morbid genes APOA1BP, ARHGEF2, LAMTOR2, LMNA, NTRK1, PRCC, RIT1, SEMA4A, and YY1AP1. Although the unique phenotype observed in our patient can arise from the haploinsufficiency of the dosage-sensitive LMNA gene, the dosage imbalance of other genes implicated in the rearrangement could also contribute to the phenotype. Further studies are required for the delineation of the phenotype associated with this rare chromosomal alteration and elucidation of the critical genes for manifestation of the specific clinical features.

Genomic Characterization of a Rare, de Novo Unbalanced ins(3;1)(p25.3;q21.3q23.3) in a Female Child with Multiple Congenital Anomalies

“…Lamin proteins are required for multiple biological processes, including normal development of peripheral nervous system and skeletal muscle, osteoblastogenesis and bone formation, and cardiac homeostasis (GeneCards database). Interestingly, submicroscopic chromosomal imbalances (1 deletion, 2 duplications) involving this gene have been observed in patients with diverse phenotypes, including microcephaly, HCC, DD/ID, dysmorphic features, and cardiac defects (with only the deletion implicated), but a direct association remains to be defined [Fichera et al, 2014;Aleksiūnienė et al, 2018;Sowińska-Seidler et al, 2018]. The fact that our patient also presents with these features may help to confirm that this gene is also triplosensitive and associated with these phenotypes.…”

Novel 1q22-q23.1 duplication in a patient with lambdoid and metopic craniosynostosis, muscular hypotonia, and psychomotor retardation

“…Out of seven genes with a high (< 10%) or moderate (< 25%) HI score ( NES , CCT3 , MEF2D , LAMTOR2 , ETV3 , SSR2 , NTRK1 ), none of them have been linked to craniosynostosis (Huang et al 2010 ). A partly overlapping deletion in the 1q22-q23.1 region has been recently described in a patient presenting with intellectual disability and multiple congenital anomalies, and two of the HI genes, NES and MAF2D , were shown to be necessary for normal neuron development in mice (Ikeshima et al 1995 ; Park et al 2010 ; Aleksiuniene et al 2018 ). Therefore, dosage imbalance could possibly contribute to mental retardation observed in the index patient.…”

Lfc/Arhgef2 regulates mitotic spindle orientation in hematopoietic stem and progenitor cells and is essential for productive hematopoiesis

“…It is interesting to note that in our Lfc/Arhgef2 -/mouse model we observe native thrombocytopenia, indicating an additional role for Lfc/Arhgef2 in regulating megakaryocyte maturation, 58,59 defects in neutrophil chemotaxis, 60 and while not formally characterized yet, bone malformations and clear neurological abnormalities (data not shown), the latter of which parallels reports of cognitive impairments and intellectual disability in patients with ARHGEF2 loss-of-function mutations. 61,62 Importantly, all of these features can be found in patients diagnosed with SDS, 63,64 which encourages future efforts to understand if the loss of ARHGEF2 function contributes to the etiology and pathogenesis of SDS.…”