P237: Diagnosis of Cornelia de Lange syndrome through EPISign whole genome methylation assay: Findings from a twin case
Year: 2024
Type: article
Study design: Case Report
Abstract: Cornelia de Lange Syndrome (CdLS; OMIM 122470) is a rare congenital multisystemic disorder caused by variants in NIPBL, SMC1A, SMC3, RAD21, and HDAC8. It is characterized by facial dysmorphism, growth restriction, developmental delay, intellectual disability, limb abnormalities, and hypertrichosis; however, the manifestations are generally heterogenous making accurate diagnosis challenging. Here we present a pediatric patient who was diagnosed with CdLS after a EPISign Whole Genome Methylation Assay through the NIH Undiagnosed Diseases Program (UDP) after clinical sequencing was nondiagnostic. The proband is a 2-year-old male born at 32 weeks gestation following apparent placental abruption. He is the product of a monozygotic, monochorionic, diamniotic pregnancy; his identical twin is healthy and typically developed. He was monitored in the NICU for 4 months for management of a cystic hygroma, fetal hydrops, and respiratory distress. His application to the UDP included a history of twin-twin transfusion syndrome, prenatal-onset disproportionate short stature, facial dysmorphism, short, webbed neck, bilateral hearing loss, gastroesophageal reflux, left foot deformity with missing fourth toe, perimembranous VSD surgically repaired, unilateral inguinal hernia and cryptorchidism. Previous microarray and exome sequencing were unrevealing. Upon admission to the UDP, this 2-year-old was noted to have eyes deviated to the left with strabismus and prominent epicanthal folds, low set posteriorly oriented ears, a right deviated septum, a short broad neck, and small but descended testicles. He was severely developmentally delayed with inability to sit independently or crawl. A renal ultrasound showed small kidneys and endocrine evaluation revealed subclinical hypothyroidism. At the conclusion of his evaluation, the child was given a clinical diagnosis of CdLS after consult with a CdLS expert. Subsequent family quintet genome sequencing was non-diagnostic. Manual review of both genome and RNA sequencing data was unable to identify a causative variant in any of the known CdLS genes. However, EPISign Whole Genome Methylation Assay identified a mildly abnormal pattern consistent with CdLS confirming the suspected clinical diagnosis. Using methylation testing in combination with exome and genome testing, we are hopeful we will identify the molecular cause of CdLS in this patient. This case highlights the utility of functional assays, such as methylation assays, to identify genetic diagnoses when sequencing is unsuccessful. Additionally, as more cases of rare and highly heterogenous conditions are identified by other related assays, careful sequencing and analysis will be required to find the causative variant and potentially reveal new disease-causing genes.
Source: Genetics in Medicine Open
Authors: Tiffany Jong, Ellen Macnamara, Cynthia Tifft
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,200
OpenAlex ID: W4392589062