Limb Development Anomalies: Genetics

Abstract

Congenital limb malformations range from reduction defects to subtle digit anomalies (number/length/anatomy). Their prevalence is evaluated from 1.3‰ to 1.9‰ neonates. They can be classified as disruption anomalies and genetic malformations. The later are due to limb development gene function alteration and may be isolated or associated with other malformations. The genes implicated in the limb bud development are numerous. They work together to trigger limb bud growth (proximodistal axis), polarisation (antero‐posterior and dorsoventral) and patterning. They are often pleiotropic, explaining the frequent association of limb anomalies with other malformations. Furthermore, limb malformations are often genetically heterogeneous and various anomalies of one single gene can cause different diseases (allelic heterogeneity). Key Concepts: The limb bud development requires a constant equilibrium between cell mitotic activity and apoptosis. The limb bud growth, its antero‐posterior and dorsoventral polarisation as well as its patterning are very interlinked and imply precise space and time regulation of the implicated genes’ expression. Regulators/enhancers : Alterations of regulatory elements of key developmental genes play an important role in limb bud development. (For example the Zone of polarising activity Regulatory Sequence (ZRS) is a crucial regulator of SHH expression in the limb bud.)

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

“…Some of them have a genetic basis and, currently, more than 150 genes or regulatory regions are known to be implicated in limb malformations (Manouvrier‐Hanu, Holder‐Espinasse, & Lyonnet, ; Manouvrier‐Hanu, Petit, Holder‐Espinasse, & Escande‐Narducci, ; Zuniga, Zeller, & Probst, ). In most cases, the responsible genetic anomaly is a single nucleotide variation (SNV) (Manouvrier‐Hanu et al, ). However, copy‐number variations (CNVs) involving genes or noncoding regulatory elements are also a major cause of CLM (Flottmann et al, ).…”

Congenital hand anomalies in Upper Egypt

“…Failure of differentiation and duplication are the most frequent anomalies with polydactyly is the most common individual diagnosis with an incidence of about 1 per 1000 live births. [ 2 8 ] This study also revealed that failure of differentiation and duplication anomalies were most frequent deformities (90.6%) with polydactyly was the most common anomaly encountered.…”

“…[ 1 ] Congenital hand anomalies rank the second most frequent malformation affecting the human body. [ 2 ] They are encountered in 0.1–0.2% of all newborns. [ 3 ] males are more commonly affected with polydactyly and syndactyly are the most common anomalies.…”

Polydactyly and genes

“…1,3,5 The identification of genes for malformation syndrome provides an opportunity to peep into the complex developmental processes involved in limb development. This is because they are caused by mutations that affect important signaling pathways repetitively used during embryonic development at different times and different locations.…”