Scientific Papers

Age of diagnosis for children with chromosome 15q syndromes | Journal of Neurodevelopmental Disorders

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Earlier identification of neurogenetic conditions is an important endeavor to improve the quality of life and long-term outcomes for individuals with the conditions, their families, and caregivers. Delayed diagnoses reduce access to early behavioral and medical interventions, prohibit surveillance for potential disease manifestations, potentially increase the severity of comorbid conditions (e.g., autism, epilepsy), and can cause an emotionally and financially challenging diagnostic odyssey for the family [1]. Early identification becomes even more critical with the potential of gene therapies that may improve outcomes or even “cure” neurogenetic conditions. These treatments hold promise to have a profound impact on the quality of life for those currently living with a neurogenetic condition at any stage of life. However, to achieve the maximum benefit, it is likely that treatment should be initiated prior to the onset of symptoms, which, depending on the condition, is likely to occur very early in life, or even during the prenatal period [2].

Prader-Willi (PWS), Angelman (AS), and duplication 15q (Dup15q) syndromes are conditions with distinct phenotypes but similar molecular origins—all originating from abnormalities within the same region at chromosome 15q11.2-q13.1. Although all three conditions have an inherited molecular subtype, the majority of cases result from de novo gene changes. Genes implicated in these three conditions are all targets for gene therapy trials, and as a result, patient advocacy organizations, clinicians, and basic scientists have combined efforts to improve therapeutic development and diagnostic processes.

Prader-Willi Syndrome occurs as a result of loss of expression of genes on the paternally inherited chromosome 15q11.2-q13. The most common mechanism resulting in PWS is a deletion of the 15q11-q13 imprinted region (60–65% of patients); maternal uniparental disomy (UPD) occurs in approximately 35% of patients; the remaining ~ 3% have an imprinting defect (ID).

The typical PWS phenotype includes hypotonia, short stature, small hands and feet, and mild to moderate intellectual disability. Behavioral issues, including symptoms of anxiety, temper outbursts, and deficits of social cognition, are also present in many individuals with PWS. Significant hypotonia at birth and feeding difficulties can lead to failure to thrive in infancy. This difficulty with feeding generally gives way to hyperphagia in early childhood, which, if not controlled, will lead to obesity and associated health issues.

Hypotonia and feeding difficulties in infancy, along with dysmorphology that is sometimes present at birth, are often causes for referral for genetic testing, thereby making PWS the most likely of the three C15 conditions to be diagnosed in the newborn period. However, infants with milder hypotonia or less common subtypes (UPD, ID) may be more likely to be diagnosed later in childhood [3].

Current first-line treatment for PWS includes growth hormone, which is most effective if initiated between 4 and 24 months of age, with physical and speech therapy starting as soon as possible. Novel therapies currently in development for PWS include those that may prove most effective when administered in the newborn period, such as oxytocin [4]. As more studies indicate more impactful outcomes for those started on treatment in early infancy, there will be increasing emphasis on earlier diagnosis. Early identification to optimize parent education and allow close monitoring of diet and behavior management strategies are also recommended.

Angelman syndrome occurs with the loss of expression from the maternally inherited UBE3A gene. In nearly three-quarters of patients, this is the result of deletion of maternal chromosome 15q11.2-q13 region. A pathogenic variant in the maternally derived UBE3A gene occurs in around 11% of patients, while paternal UPD occurs in around 8% and an imprinting defect in around 7% [5].

The phenotype of AS is characterized by severe to profound intellectual disability, minimal or absent verbal speech, seizures, ataxia, and an easily excitable, happy demeanor. Symptoms of anxiety, short attention span, and difficulty with sleep are also commonly experienced. Although symptoms of AS often begin within the first year of life, symptoms are not obvious at birth and early features can be mistaken for other forms of developmental delay (e.g., autism, cerebral palsy [6]).

The treatment landscape for AS has changed dramatically over the last decade. Historically, the only treatment options were symptom-based (e.g., seizure medication, behavior management), and new discoveries in UBE3A function and mechanisms for gene therapy now suggest that disease-modifying therapies may be imminent. Clinical trials testing the safety and efficacy of these therapeutics are currently in progress; positive results are likely to rapidly lead to increased urgency in earlier identification to maximize treatment outcomes.

Dup15q syndrome also involves the PWS/AS critical region, but in contrast to PWS and AS, it is caused by overexpression of genes within the region, usually the result of at least one extra maternally derived copy of the region. In isodicentric Dup15q (Idic15; the most common of two forms), a small supernumerary chromosome with two extra copies of the maternal 15q11.2-q13 region is present in addition to two normal chromosomes 15. This results in individuals having three maternal copies and one paternal copy of the locus. The other form of Dup15q, maternal interstitial duplication, involves one extra copy of the maternal 15q11.2-q13 region, resulting in two maternal copies and one paternal copy of the locus. Paternally derived duplications of 15q11.2-q13 have also been reported, although the resulting phenotype is variable and less well characterized [7].

Of the three C15 conditions, Dup15q is thought to have the most heterogeneous presentation, which may contribute to later diagnoses [8]. However, primary features overlap with both AS and PWS, including hypotonia, mild to severe intellectual disability, seizures, and high rates of comorbid autism. Several studies have indicated that individuals with Idic15 have more severe phenotypes than those with interstitial duplications [8, 9].

In part because of the molecular overlap, diagnostic and treatment efforts for Dup15q overlap significantly with efforts for AS and PWS. However, primary treatment recommendations currently are primarily symptom-focused (e.g., seizure management, behavioral/educational therapies). Drug discovery and gene therapy efforts are underway for Dup15q but are further behind than those for AS or PWS.

Diagnostic processes

Although guidelines exist from professional organizations such as the American Academy of Pediatrics and the American College of Medical Genetics, there remain inconsistencies in how and when children are referred for genetic testing. Diagnostic evaluations of young children with a C15 condition nearly always result from the onset of symptoms, but the process can vary significantly based on the condition, clinical presentation, molecular subtype, and knowledge on the part of the evaluating healthcare professional. For some individuals, PWS or AS may be in the differential because of a phenotypic presentation consistent with the diagnosis. The stepwise diagnostic approach for these patients can differ from clinic to clinic, but typically begins with DNA methylation testing via PCR, Southern hybridization, or MS-MLPA chromosome 15 testing [10]. An abnormal methylation result is diagnostic of AS or PWS but will require additional testing to characterize the underlying molecular subtype. Not all individuals with suspected AS will have abnormal DNA methylation results, and in these individuals, UBE3A sequencing is necessary. In PWS, nearly all (> 99%) will be positive based on DNA methylation analysis.

For individuals with a C15 disorder who present with nonspecific features that are not clearly suggestive of PWS or AS, such as developmental delay, seizures, mild hypotonia, or autism, chromosome analysis or chromosomal microarray (CMA) may be ordered as first-tier diagnostic tests [11, 12]. CMA utilizing either oligonucleotide or single-nucleotide polymorphism (SNP) probes will detect Dup15q but cannot differentiate between isodicentric chromosome 15 and an interstitial duplication. Chromosome analysis is needed to identify the supernumerary isodicentric chromosome 15 but is not able to identify most interstitial duplications seen in individuals with Dup15q. Therefore, to achieve an accurate molecular diagnosis, a combination approach including both chromosome analysis and CMA is needed. Because the phenotype may differ depending on the parent of origin, methylation analysis can be pursued to determine if the duplication was maternally or paternally derived [13].

CMA will also detect chromosome 15 deletions associated with AS and PWS. However, only SNP arrays have the ability to detect loss of heterozygosity, which can identify patients with chromosome 15 uniparental disomy (UPD15) resulting from segmental or total isodisomy [13]. Thus, SNP arrays will not be diagnostic for patients with UPD15 because of heterodisomy, nor for those with imprinting centers due to epimutations or microdeletions below the level of resolution for CMA. Patients who remain undiagnosed after CMA may go on to receive additional testing until a diagnosis is eventually established.

This diagnostic odyssey, which mirrors the experiences of many individuals with rare neurogenetic conditions, may take years, which can result in high financial and emotional stress for families and delayed start of treatment for the children. Identifying current trends in the age of diagnosis for a condition can help to establish strategies for reducing delays and potentially improving prognoses. The goal of the current study was to describe the distribution of age of diagnosis for C15 conditions, including differences within and across conditions and potential trends across the last 10 years.

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