medwireNews: Researchers have identified novel pathogenic variants that may account for approximately 9% of children with Silver–Russell syndrome (SRS) who have not previously had a molecular diagnosis and aid understanding of the relationships between genotype and phenotype.
Clinical diagnosis of SRS is based on the presence of at least four of the six clinical signs in the Netchine–Harbison Clinical Scoring System (NH-CSS) and molecular testing confirms this diagnosis in around 60% of patients, explain Silvia Russo, from IRCCS Istituto Auxologico Italiano in Milan, Italy, and co-workers.
However, approximately 40% of children with suspected SRS do not have a known imprinting alteration or a recognised variant of the SRS genes IGF2, PLAG1, HGA2 or CDKN1C, the authors say in the Journal of Clinical Endocrinology & Metabolism.
To investigate further, the team conducted genetic analyses in 132 children without (epi)genetic deregulations but with a clinical diagnosis of SRS based on the NH-CSS criteria.
Overall, pathogenic variants were identified in 9.1% of this cohort, report Russo et al.
Whole-exome sequencing gave a confirmed diagnosis of SRS or another disorder for six of 15 unrelated patients. Specifically, these included SRS in a child with an inherited mutation in PLAG1 and SRS differential diagnoses in two children with an inherited or de novo alteration in IGFR1. Among the remaining three children, one had an autosomal recessive alteration in CCDC8 and was diagnosed with 3-M syndrome type 3, one had an alteration in SBDS and was diagnosed with Schwachman-Diamond syndrome type 1, and one had a de novo variant of FGFR3 and was diagnosed with hypochondroplasia.
An additional two patients had “uncertain diagnoses”, the researchers say. The first patient had a compound heterozygous genotype of both a pathogenic alteration and a variant of unknown significance in BRAT1 that is linked to NEDCAS syndrome. The second child inherited a variant of unknown significance in CHD7 that has previously been linked to CHARGE syndrome.
Further investigation subsequently detected a de novo deletion of CRX in a child that was associated with cone-rod retinal dystrophy-2 alongside a partial deletion of the BICRA gene that is linked to Coffin-Siris syndrome 12.
Meanwhile, targeted sequencing of the SRS genes IGF2, PLAG1 and HMGA2 in 117 patients identified three novel genetic variants: an inherited IGF2 splicing variant, a nonsense variant of HMGA2 and an in-frame deletion variant of PLAG1. Sequencing of the IGF1R gene, associated with insulin-like growth factor (IGF)-1 resistance, in the remaining 114 patients, revealed two likely inherited pathogenic variants and one variant of unknown significance.
Russo and co-workers also examined the relationship between the genetic alterations and SRS phenotype.
They note that children with PLAG1, HMGA2 and IGF1R alterations were significantly less likely to have relative macrocephaly at birth than those with IGF2 variants (44, 40, 20 vs 77%, respectively) as well as body asymmetry (0.0%, 5%.0, 1.5% vs 25.0%). By contrast, IGF2 variants were associated with significantly higher frequencies of difficulties with feeding, heart and skeletal complications, and developmental delay than the other alterations.
“The clinical review of the reported cases shows overlapping features between SRS and IGF-1 [resistance] patients, as well as the presence of some differences”, the authors conclude. “This evidence prompted us to include IGFR1 sequencing in the diagnostic workup for SRS.”
Finally, the team highlights that there was a high number of familial cases in their study, affecting 28%, 60%, 78% and 89% of patients with alterations to IGF2, HMGA2, PLAG1 and IGF1R, respectively, and that while 40–100% of parents were symptomatic, 60% of those with a familial IGF2 alteration and 18% of those with a familial IGFR1 alteration were not.
Russo and co-authors therefore conclude that “due to the significant number of documented familial cases, with parents not necessarily displaying the phenotype, clinical parental studies and genetic counselling are recommended.”
By Lynda Williams
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