Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy

Abstract

Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care.

Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy

“…However, frameshift and nonsense variants resulting in protein truncation (5.7%) are far less common than missense variants (63.7%). This pattern of genetic variation is reminiscent of ALMS1 and the specificity for recessive truncating mutations as a cause for Alström syndrome (OMIM 203800), a syndromic form of pediatric DCM . Individuals with compound heterozygous mutations cannot be determined from the ExAC database.…”

De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy

“…The mean age at diagnosis is 45 years (Michels et al 1992), but a subset of patients become clinically symptomatic in childhood. Furthermore, some children develop DCM and advanced heart failure in the absence of myocardial disease in their adult parents (Long et al 2015; Long et al 2015). Diagnosis of sporadic DCM in an infant or child should prompt a broad differential diagnosis and testing for reversible causes of heart failure, yet it remains an idiopathic disorder in 66% of children (Towbin et al 2006).…”

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

“…When this approach did not reveal any mutation, an array‐based technology, which includes a set of known mutations in ALMS1 , was often carried out . Nevertheless, as the NGS methodology is rapidly growing and gradually replacing abovementioned technologies, whole‐exome and whole‐genome sequencing are nowadays the most widely used approaches to identify the causal mutation and secondly also exclude mutations in other genes in the differential diagnosis …”

“…124,128 Nevertheless, as the NGS methodology is rapidly growing and gradually replacing abovementioned technologies, whole-exome and whole-genome sequencing are nowadays the most widely used approaches to identify the causal mutation and secondly also exclude mutations in other genes in the differential diagnosis. 124,142,143 As for PWS and BBS, the only therapy for AS patients is restricted to the management of the clinical symptoms and the improvement of the quality of life. 124 Between birth and age 15 months most patients become very sensitive to light (photodysphoria) which can be reduced with the use of red-orange tinted lenses.…”