Autistic and Rett‐like features associated with 2q33.3–q34 interstitial deletion

Abstract

We describe the fourth reported case of a de novo 2q33.3-q34 interstitial deletion and review the literature in attempt to identify relevant candidate genes. A 15-month-old female patient presented for evaluation with poor eye contact and developmental delay. She had microcephaly and mild dysmorphic features, such as downslanting palpebral fissures, high forehead, small mouth, high palate, and general hypotonia. At 30 months of age, she was referred to the genetic clinic for an evaluation of persistent developmental delay, autistic traits, and Rett-like features, including bruxism and repetitive movement of the left hand. Chromosome analysis revealed 46,XX at the 550 band level. No abnormalities were found on analysis of MECP2 gene for Rett syndrome and a DNA methylation test for Prader-Willi syndrome. An array comparative genomic hybridization analysis revealed a de novo 2q33.3-q34 heterozygous deletion (206,048,173-211,980,867). The deletion was estimated to be 5.9 Mb in size and contained 34 known genes. Candidate genes were identified as NRP2, ADAM23, KLF7, CREB1, MAP2, UNC80, and LANCL1 for the 2q33.3-q34 interstitial deletion.

De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability, neuromuscular and psychiatric symptoms

“…The additional individual present in ClinVar was reported with at least ID. These characteristics are similar to the individuals reported with the 2q33.3q34deletion syndrome, although the phenotype is also highly variable (reviewed in Table ) . Of the 4 previously reported patients in the literatures with the deletion, varying degrees of DD/ID, hyptonia, feeding/swallowing issues, psychiatric features and neuromuscular issues were reported along with dysmorphic features, seizures and microcephaly.…”

“…Emerging evidence suggests that KLF7 haploinsufficiency results in a recognizable neurodevelopmental phenotype. Located at 2q33.3, KLF7 has been proposed to be one of the possible candidate genes for the phenotype associated to the 2q33.3q34 deletion which has been reported in patients with ASD . Additionally, these patients present with microcephaly, hypotonia, psychomotor retardation and mild dysmorphic features.…”

Genetic variation associated with chromosomal aberration frequency: A genome‐wide association study

“…The second SNP from the CAtot analysis, rs2824215 (21q21.1) is located in a long intergenic noncoding RNA (LiNC), and deletion in this locus has been linked to autistic features with complex chromosomal rearrangements (Haldeman-Englert et al 2010). Interestingly, two other SNPs, which we selected for replication, rs17215792 (2q33.3) and rs2837619 (21q22.2) are located in the genes associated with autism and Down syndrome, KLF7 (Kruppel like factor 7) (Pescucci et al 2003;Jang et al 2015) and DSCAM (Down Syndrome Cell Adhesion Molecule), respectively (Yamakawa et al 1998;Cvetkovska et al 2013). Chromosomal abnormalities are an important feature of both diseases (Liao et al 2013).…”

2q33.1q34 Deletion in a Girl with Brain Anomalies and Anorectal Malformation

“…NRP2 mediates axon guidance and neuronal migration; ADAM23 is involved in neuronal migration; KLF7 controls neuronal morphogenesis; and CREB1 plays a key role in synaptic plasticity. Therefore, all these genes might be candidates for the neurologic phenotype observed in all of the described cases as well as in our patient [Jang et al, 2015]. Hemizygosity of ABI2, CYP20A1 , and ALS2 has been linked to the behavioural problems, particularly to hyperactivity [Mencarelli et al, 2007].…”