<b><i>HDAC8</i></b> Loss of Function and <b><i>SHOX</i></b> Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype

Abstract

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.

Landscape of Constitutional SOX4 Variation in Human Disorders

“…Furthermore, "expansion" of the clinical spectrum of a known disorder may often hide a dual molecular diagnosis [46], as variants in other genes can modify the clinical phenotype. At least two patients with SOX4 pathogenic variants were reported to carry a causative variant in a distinct gene (F11, TTN); others had VUS that may contribute to the phenotype.…”

Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications

“…Classic CdLS can be easily diagnosed from birth because of distinctive craniofacial appearance and growth pattern and limb malformations, while other patients show variant clinical features characterized by different degrees of facial and limb involvement (Kline et al, 2018). Interestingly, heterozygous HDAC8 frameshift mutation is shown to co-exist with SHOX haploinsufficiency that cause more complexed clinical features (Severi et al, 2019). It is also shown that HDAC8 and HDAC2 are expressed in hypertrophic chondrocytes and knockdown of HDAC2/3/8 increases SOX9 and decreased RUNX2 expression (Chen W. et al, 2016).…”