Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor

Abstract

The 2q37 deletion syndrome, also described in the literature as brachydactyly-mental retardation syndrome (MIM 600430), is caused by deletion or haploinsufficiency of the HDAC4 gene, which encodes the histone deacetylase 4 protein. Although the most commonly described hallmark features of the 2q37 deletion syndrome include brachydactyly type E, developmental delay, obesity, autistic features, and craniofacial or skeletal dysmorphism, a literature review of 101 published cases plus two newly reported individuals indicates that there is a high degree of variability in the presence of some of the features that are considered the most characteristic of the syndrome: overweight and obesity (34%), cognitive-behavioral issues (79%), dysmorphic craniofacial features (86%), and type E brachydactyly (48%). These features overlap with other neurodevelopmental conditions, including Smith-Magenis syndrome (SMS), and may be incompletely penetrant or demonstrate variable expressivity, depending on the specific chromosomal anomaly. With the advent of fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization, and next-generation DNA sequencing, more detailed molecular diagnoses are possible than in years past, enabling refined characterization of the genotype-phenotype correlation for subjects with 2q37 deletions. In addition, investigations into molecular and gene expression networks are expanding in neurodevelopmental conditions, and we surveyed HDAC4 downstream gene expression by quantitative real-time polymerase chain reaction, further implicating HDAC4 in its role in the regulation of RAI1. Correlation of clinical data defining the impact on downstream gene expression and the potential clinical associations across neurodevelopment will improve our understanding of these complex conditions and potentially lead to common therapeutic approaches. K E Y W O R D Sautism spectrum disorder, behavioral disturbances, brachydactyly type E, developmental delay, HDAC4, obesity

Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations

“…Patients with 2q37 deletion syndrome, also described in the literature as Albright hereditary osteodystrophy‐like syndrome or brachydactyly‐mental retardation (BDMR) syndrome, suffer from mental retardation, facial dysmorphism, including round face and flattened nasal bridge, and skeletal abnormalities such as brachydactyly and short stature 72‐74 . More than 100 cases have been reported in the literature with 2q37 deletion syndrome 75 . Genotype–phenotype correlation studies have been performed to delineate the critical region causing BDMR 75 .…”

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees

“…Although we are not able to confidently make causal statements, overcoming this formidable obstacle will require the accumulation of phenotype and genotype information afforded by in‐depth studies such as ours. Such variable penetrance is widely recognized in ASD and other neurodevelopmental disorders (Bateman et al, 2018; Le, Williams, Alaimo, & Elsea, 2019; Ropers & Wienker, 2015), even at “high risk” neurodevelopmental loci. For example, the well‐described 2q37 deletion syndrome is associated with a wide range of neurodevelopmental and medical phenotypes, and it is only by considering size and position of CNV along with downstream expression of underlying genes and their interacting partners, that the relationship of genotype to phenotype is more fully appreciated (Le et al, 2019).…”

“…Such variable penetrance is widely recognized in ASD and other neurodevelopmental disorders (Bateman et al, 2018; Le, Williams, Alaimo, & Elsea, 2019; Ropers & Wienker, 2015), even at “high risk” neurodevelopmental loci. For example, the well‐described 2q37 deletion syndrome is associated with a wide range of neurodevelopmental and medical phenotypes, and it is only by considering size and position of CNV along with downstream expression of underlying genes and their interacting partners, that the relationship of genotype to phenotype is more fully appreciated (Le et al, 2019). Moreover, similar to ours, other studies have also found variable penetrance for identical mutations in family members of identified probands (Bateman et al, 2018).…”

Knockout of the gene encoding the extracellular matrix protein SNED1 results in early neonatal lethality and craniofacial malformations

“…[69][70][71] More than 100 cases have been reported in the literature with 2q37 deletion syndrome. 72 Genotype-phenotype correlation studies have been performed to delineate the critical region causing BDMR. 72 HDAC4 has been postulated as one of the candidates responsible for BDMR.…”