Deletion 2q37 syndrome: Cognitive‐behavioral trajectories and autistic features related to breakpoint and deletion size

Abstract

Subtelomeric deletions have been reported in ∼2.5% of individuals with developmental disabilities. Subtelomeric deletion 2q37 has been detected in many individuals diagnosed with intellectual disabilities (ID) and autism spectrum disorders (ASD). Previously, genotype-phenotype correspondences were examined for their relationship to breakpoints 37.1, 37.2, or 37.3. Our purpose was to ascertain whether there were phenotypic differences at these breakpoints, elucidate the cognitive-behavioral phenotype in del2q37, and examine the genotype-phenotype association in the deletion with respect to cognitive-behavioral profiles and ASD. We administered a comprehensive cognitive-behavioral battery to nine children diagnosed with del 2q37, ages 3.9-17.75 years. ID for five tested with the Stanford-Binet (4th Edition) (SBFE) ranged from severe to mild [IQ Range: 36-59]. Adaptive behavior scores from the Vineland Adaptive Behavior Scale (VABS) were much below adequate levels (DQ Range: floor value ["19"] to 55). Autism scores from the Child Autism Rating Scale (CARS) ranged from 22 [non-autistic] to 56 [extremely autistic]; 5/8 [63%] children received scores on the autism spectrum. Participants with the largest deletions, 10.1 and 9.5 Mb, attained the highest IQ and DQ scores while those with the smallest deletions, 7.9 and 6.6 Mb, made the lowest IQ and DQ scores. No association between deletion breakpoint and phenotype were found. Assessment of the various deleted regions suggested histone deacetylase 4 gene (HDAC4) was a likely candidate gene for ASD in our sample. However, two earlier reports found no association between HDAC4 haploinsufficiency and ASD. © 2016 Wiley Periodicals, Inc.

Aberrant Expression of Histone Deacetylases 4 in Cognitive Disorders: Molecular Mechanisms and a Potential Target

“…Several lines of evidence suggests that dysregulation of HDAC4 is implicated in ASD (Pinto et al, 2014; Fisch et al, 2016). First, HDAC4 mRNA was significantly increased in autistic brains (Nardone et al, 2014).…”

2q37 deletion syndrome in a Colombian patient with macrocephaly: a case report

“…1 ) including the HDAC4 gene which is one of the most important genes driving the symptoms in del2q37 patients [ 6 ]. Furthermore, there is no clear association with length of deletion (as previously hypothesized) and clinical phenotype; even more, larger deletions (9.5 and 10.1 Mb) have been associated with higher IQ whereas smaller deletion with lower IQ (6.6 and 7.9 Mb) [ 11 ]. Deleted genes in our patients also include genes that, in homozygosis, have been associated with different syndromes and pathologies (Table 1 ) such as Bethlem myopathy 1 (gene COL6A3), advanced sleep phase syndrome (PER2), Barber-Say syndrome (TWIST2) and susceptibility to type 2 diabetes mellitus 1 (CAPN10) as reported in OMIM database.…”