Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis.

Pathogenic PHF21A variation causes PHF21A-related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in-frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A-related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice.

Do PACS1 variants impeding adaptor protein binding predispose to syndromic intellectual disability?

To date, PACS1-neurodevelopmental disorder (PACS1-NDD) has been associated with recurrent variation of Arg203 and is considered diagnostic of PACS1-NDD, an autosomal dominant syndromic intellectual disability disorder. Although incompletely defined, the proposed disease mechanism for this variant is altered PACS1 affinity for its client proteins. Given this proposed mechanism, we hypothesized that PACS1 variants that interfere with binding of adaptor proteins might also give rise to syndromic intellectual disability. Herein, we report a proposita and her mother with phenotypic features overlapping PACS1-NDD and a novel PACS1 variant (NM_018026.3:c.[755C > T];[=], p.(Ser252Phe)) that impedes binding of the adaptor protein GGA3 (Golgi-associated, gamma-adaptin ear-containing, ARF-binding protein 3). We hypothesize that attenuating PACS1 binding of GGA3 also gives rise to a disorder with features overlapping those of PACS1-NDD. This observation better delineates the mechanism by which PACS1 variation predisposes to syndromic intellectual disability.

Reduced Growth Hormone Response to Anaerobic Exercise Among Children With Overweight and Obesity.

ABSTRACT: Hejla, D, Dror, N, Pantanowitz, M, Nemet, D, and Eliakim, A. Reduced growth hormone response to anaerobic exercise among children with overweight and obesity. J Strength Cond Res 36(8): 2194-2197, 2022-The aim of the present study was to examine the effect of an anaerobic exercise test on growth hormone (GH) secretion in children with overweight and obesity compared with children with normal weight. Fifteen children with overweight (body mass index percentile [BMI%ile] ≥85 < 95) and obesity (BMI%ile ≥95) and 10 children with normal weight (BMI%ile >5 < 85) participated in the study. Subjects performed a modification of the Wingate anaerobic test (WAnT), with 10 bouts of 15-second cycling separated by 1 minute of rest. Blood samples for GH and lactate were collected before and 15, 30, 45, and 60 minutes after the beginning of the exercise test. There was a significant increase in GH levels following the modified repeated WAnT in both groups, but the increase in GH levels was significantly greater among the normal weight children compared with those with overweight and obesity ( p < 0.003). Seven of the 10 subjects with normal weight had GH increase above the threshold for GH sufficiency compared with only 2 subjects with overweight and obesity. Growth hormone response to the modified repeated WAnT was significantly reduced among children with overweight and obesity compared with those with normal weight. Anaerobic interval-type training may not be a sufficient exercise alternative to stimulate appropriate GH levels among children with obesity.