Sequence variants in muscle tissue‐related genes may determine the severity of muscle contractures in cerebral palsy

Abstract

Muscle contractures are a common complication to cerebral palsy (CP). The purpose of this study was to evaluate whether individuals with CP carry specific gene variants of important structural genes that might explain the severity of muscle contractures. Next‐generation‐sequencing (NGS) of 96 candidate genes associated with muscle structure and metabolism were analyzed in 43 individuals with CP (Gross Motor Function classification system [GMFCS] I, n=10; GMFCS II, n=14; GMFCS III, n=19) and four control participants. In silico analysis of the identified variants was performed. The variants were classified into four categories ranging from likely benign (VUS0) to highly likely functional effect (VUS3). All individuals with CP were classified and grouped according to their GMFCS level: Statistical comparisons were made between GMFCS groups. Kruskal‐Wallis tests showed significantly more VUS2 variants in the genes COL4 (GMFCS I–III; 1, 1, 5, respectively [p < .04]), COL5 (GMFCS I–III; 1, 1, 5 [p < .04]), COL6 (GMFCS I–III; 0, 4, 7 [p < .003]), and COL9 (GMFCS I–III; 1, 1, 5 [p < .04]), in individuals with CP within GMFCS Level III when compared to the other GMFCS levels. Furthermore, significantly more VUS3 variants in COL6 (GMFCS I–III; 0, 5, 2 [p < .01]) and COL7 (GMFCS I–III; 0, 3, 0 [p < .04]) were identified in the GMFCS II level when compared to the other GMFCS levels. The present results highlight several candidate gene variants in different collagen types with likely functional effects in individuals with CP.

The NESHIE and CP Genetics Resource (NCGR): A database of genes and variants reported in neonatal encephalopathy with suspected hypoxic ischemic encephalopathy (NESHIE) and consequential cerebral palsy (CP)

“…One of the catalogued COL4A1 variants with predicted deleteriousness, NM_001845:c.2263G > A, occurred in a patient with CP due to birth asphyxia, which describes a hypoxic event that may lead to NESHIE and potentially to CP [ 82 , 97 ]. In addition to variants in COL4A1, variants in another gene that forms part of the COL4 family namely, COL4A4, have also been reported in patients with CP [ 96 , 98 ]. Notably, the COL4A4 stop-gain variant, NM_000092.5:c.4720C > T, was reported in a patient with CP as a result of NESHIE [ 96 ].…”

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

“…Escobar syndrome has been reported in 101 patients in 72 pedigrees [ 35 , 36 , 38 , 45 , 146 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ]. As the γ subunit is substituted for the ε subunit after birth, patients show no myasthenia or muscle weakness, but is classified into a form of CMS [ 36 ].…”

Congenital cerebral palsy: genetic cause and nosological integrity

“…Pingel и соавт. при исследовании возможной генетической детерминированности специфических особенностей обмена мышечной ткани, способствующей выраженному контрактурообразованию, выделили у больных спастическими формами ЦП типы коллагена, в большей степени заинтересованные в контрактурообразовании (4, 5, 6 и 9-й типы), и кодирующие их гены-кандидаты [52].…”