Deciphering Clues to Genotype-Phenotype Correlation
Editorial
The beginning of the era of mutation detection in clinical practice was very exciting. Some ‘lumped’ phenotypes got
separated while some disorders with great phenotypic similarities were either found to be allelic or disorders sharing a
common pathway. One gene and multiple phenotypes was found to be not uncommon. Incomplete penetrance and variable
expression did not remain concepts and observations but had molecular evidence to support them. Intrafamilial variability
more common with autosomal dominant disorders but also seen in autosomal recessive disorders led to the search for
modifier genes. Interaction between alpha and beta globin genes provided some insights into the genotype-phenotype
correlations of thalassemia intermedia. Null alleles, specific locations of mutations and gain-of-function
mutations provided some genotype-phenotype correlations in beta thalassemia, osteogenesis imperfecta,
etc. Specific single causative mutation responsible for the disease in concern has been observed in very
few disorders such as sickle cell disease, type V osteogenesis imperfecta, and Caffey disease. In certain
others such as achondroplasia, Apert syndrome and Hutchinson-Gilford progeria syndrome, one or a few
mutations have been found to account for majority of the cases. Some correlation based on the nature and
position of the mutation is understood, such as out-of-frame/ frameshifting deletions in the dystrophin
gene leading to the more severe phenotype of Duchenne muscular dystrophy versus the in-frame deletions
causing the less severe phenotype of Becker muscular dystrophy. However, this alone cannot explain the
phenotypic variation in all cases. In general, for most of the disorders no genotype-phenotype correlation is
observed.
Genetic heterogeneity and phenotypic heterogeneity are challenges in clinical practice. Next generation
sequencing-based diagnostics have provided solutions to some extent to the genetic heterogeneity. However, prediction of
phenotype continues to remain a big question even for known pathogenic variations. One of the most important causes of
marked phenotypic variability observed in females with fragile X syndrome is lyonization leading to mosaicism for the
mutated and fully methylated allele of FMR1 gene. Mosaicism for number of repeats and mosaicism for methylation of
FMR1 promoter has been observed in males. The methylation status of FMR1 gene promoter has shown correlation with
FMR1 mRNA and neurodevelopmental dysfunction. The GenExpress of this issue discusses the use of methylation of
FMR1 gene promoter in samples of newborn screening, for diagnosis and prognostication. Many genes involved in
chromatin modelling influence the expression of many other genes, and mutations in these genes thus cause
phenotypic abnormality due to changes in the expression of genes under their control. The modification
of methylation of many genes in the genome by pathogenic sequence variations in genes for monogenic
syndromes like Coffin-Siris syndrome, Rubinstein-Taybi syndrome, etc. has been reported in recent literature.
Research in this area has successfully provided specific methylation signatures of these monogenic disorders.
Studies of correlation of the expression of genes with modified methylation, sequence variation in concern and
the phenotypes, will be useful in classifying novel sequence variations as pathogenic or non-pathogenic,
and also may provide insights into genotype-phenotype correlations. The GenExpress in this issue also
mentions another interesting study on differentially methylated regions (DMRs) that undergo demethylation
in late gestational age in cord blood cells, which can be used to correctly assess the gestational age of a
neonate.
As next-generation sequencing is coming into clinical practice for population-based screening for carriers of
recessive disorders and for newborn screening for early-onset serious genetic disorders, there is a strong
need to find out genetic modifiers so as to go into the depth of genotype-phenotype correlation. Not only
sequence variations in the genome and genes of the pathway or protein complexes but the various epigenetic
mechanisms affecting gene expression may provide clues to the unanswered questions of genotype-phenotype
correlations.
