American Journal of Medical Genetics Part A最新文献

Few studies describe the impact of rapid exome sequencing (ES) on pediatric cardiomyopathy in urgent clinical settings. Here, we retrospectively report the impact of rapid singleton ES in pediatric patients presented with acute heart failure and isolated cardiomyopathy or myocarditis, between 2021 and 2023 at a single tertiary care center. A total of nine patients were included; age range: 5 days-11 years (median 42 days). Eight patients (88.8%) presented in the first year of life. The turnaround time for the ES results was 5-14 days (median 9 days). The diagnostic yield was 5/9 (55.5%), confirming primary cardiomyopathy. The majority had dominant disorders (ACTC1, MYBCP3, TNNI3, and NKX2-5), with two (22.2%) occurring de novo. One patient had a recessive condition (MYBPC3). In three patients (33.3%) who rapidly deteriorated during hospitalization, ES results had a major impact on immediate medical management. In most patients, the diagnosis led to the avoidance of further metabolic workup, cardiac magnetic imaging and vitamin treatment. In two families with no prior history of cardiomyopathy, at-risk relatives were advised to initiate cardiac surveillance. Overall the results show high clinical impact due to a shorter time to diagnosis, a high diagnostic yield, an improved therapeutic approach, in addition to the facilitation of genetic counseling for family planning and cascade testing of relatives at risk.

Pathogenic variants in the SCN5A gene and its subunits have been identified in individuals with Brugada Syndrome. One such SCN5A variant, c.689T>C(p.Ile230Thr), was previously reported as disease-causing only in homozygous individuals, with heterozygous carriers being unaffected. Presently, we discuss the case of an adolescent patient who presented for further evaluation of pre-syncopal episodes with ECG findings consistent with Brugada pattern who on further genetic evaluation was found to be a heterozygous carrier of the pathogenic SCN5A c.689T>C(p.Ile230Thr) variant. This unique case allows us to think differently about heterozygous carriers for this specific mutation, and while the risk for developing a life-threatening arrhythmia may be low, heterozygous carriers may benefit from clinical monitoring to reduce the potential for adverse cardiac outcomes. A 17-year-old male presented after a pre-syncopal episode whose ECG demonstrated sinus bradycardia and type 1 Brugada pattern. Genetic testing revealed this patient to be a heterozygous carrier of a pathogenic SCN5A variant (c.689T>C(p.Ile230Thr)) which was also found in his father and brother, neither of whom had symptoms but did have ECG changes. He was diagnosed with Brugada Syndrome and advised to avoid known triggers. This case highlights the potential risk of severe cardiac arrhythmias in heterozygous carriers of the SCN5A c.689T>C (p.Ile230Thr) variant, previously thought to be benign. The 17-year-old patient, along with his asymptomatic father and brother who also carried the variant, exhibited ECG changes consistent with Brugada pattern. This finding suggests that heterozygous carriers may require closer monitoring and early intervention to prevent future life-threatening cardiac events.

Congenital myopathy-14 (CMYO14) is an ultrarare autosomal recessive disorder caused by biallelic variants in MYL1, with only four patients reported to date. We describe what is likely the fifth reported patient, a neonate with severe hypotonia, respiratory insufficiency, and skeletal anomalies showing distinct histological changes of skeletal muscle consistent with all previously described patients. The patient carried a novel homozygous intron variant (c.479-25T>C, p.(?)) in MYL1. RNA analysis of patient muscle demonstrated aberrant splicing, with inclusion of 19 bp from intron 4 in most transcripts, resulting in a frameshift and premature stop codon, and in-frame skipping of exons 4-5 in a minority of transcripts encompassing functional domains. In addition to core CMYO14 features, the patient presented with craniofacial anomalies not previously described. This case broadens the genotypic and phenotypic spectrum of MYL1-related disease and underscores the diagnostic importance of intron variants, highlighting the value of combining in silico splice prediction with functional RNA analyses.

Genetic conditions suspected in children often require genetic testing for accurate diagnoses, but testing remains costly. Case management teams review genetic test requests to improve access for patients while reducing the financial burden for medical institutions. Limited data exist on the diagnostic yields of genetic testing in the inpatient versus outpatient setting and the impact to care denial of inpatient genetic testing may pose. This study investigates diagnostic yields between patients approved for versus denied inpatient genetic testing and its impact to care. One thousand and fifty-two charts of children admitted inpatient who received a genetic consult between July 2018 and June 2023 were reviewed; charts of children that followed up at the outpatient genetics clinic after inpatient discharge were additionally reviewed. Collected data included recommendations, completion, and results of genetic testing, and management recommendations based on a diagnosis. Statistical analysis assessed differences between the groups. Private insurance holders and patients with no prematurity history were less likely to be approved for inpatient genetic testing. The outpatient group had nearly twice the diagnostic yield and management recommendations did not differ between the groups. Inclusion of genetic providers in the review of inpatient genetic testing requests should be considered to improve outcomes.

The pediatric Down syndrome (DS) clinic model improves medical care access and treatment; however, evidence-based outcomes of this model implementing routine screening are not well documented. Our goal was to evaluate the impact of the pediatric DS clinic on the identification of children with DS and celiac disease using a large patient population. This is a retrospective review of a large cohort of children with DS ages 3-22 years (total = 4158; 2011-2024 Sie Center for DS [SCDS] patients = 2164; 2011-2024 Children's Hospital Colorado [CHCO] patients with DS not seen at SCDS = 924; 1998-2010 CHCO patients with DS receiving care at CHCO before the SCDS = 1070) at a large pediatric hospital. Symptoms present, type and frequency of testing completed, and other co-occurring conditions were reviewed. The pediatric DS clinic model using routine screening significantly increased the identification of celiac disease (7.4%, n = 160/2164 vs. 2.4% and 2.8%) with the majority identified by routine screening rather than current American Academy of Pediatrics (AAP) DS Guidelines' recommendations. Impact of repeat screenings and co-occurring condition risk ratios is reported. The pediatric DS clinic model implementing routine screening improves patient identification for celiac disease. Our results should be considered when updating celiac disease testing recommendations in the AAP DS Guidelines for this unique population.

Noonan syndrome (NS) and the clinically related Noonan syndrome with multiple lentigines (NSML) belong to the group of RASopathies. Although pain is not mentioned as a characteristic feature, it has recently been reported as a clinically significant problem. This pain is likely multifactorial in origin, with a significant contribution from neuropathic mechanisms. Patients with NS also have a high chance of having multifocally enlarged nerves, and sometimes show clinical features of neuropathy. The relationship between these nerve findings, pain, health-related quality of life and neurological symptoms remains unclear. This case series aims to provide more insight into the perceived health-related quality of life and neurological symptoms in nine adults with NS or NSML who reported neuropathic pain and had enlarged nerves. Features of some of these patients were already reported in an earlier article. The perceived health-related quality of life was markedly below average. All patients reported somatosensory symptoms consistent with peripheral neuropathy. Six of nine patients reported muscle weakness. Sensory testing was abnormal in five patients, but muscle strength was normal in all patients. Electrodiagnostic testing was consistent with peroneal neuropathy in one patient, muscle and nerve ultrasound imaging confirmed neuromuscular involvement in five of the six patients who reported muscle weakness. No muscle ultrasound imaging was performed in the sixth patient. This study thus shows that adults with NS and NSML with neuropathic pain and enlarged nerves have a significantly impaired perceived health-related quality of life with a variable clinical neurologic phenotype.

Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.

Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previously unreported homozygous nonsense variant in ALMS1: c.4740C>G (p.Tyr1580Ter), located in exon 8, a known hotspot for pathogenic variants. The variant aligns with the loss-of-function mechanism seen in most ALMS1-related AS cases and is found within a 15 Mb run of homozygosity, consistent with her history of parental consanguinity. Her clinical picture included progressive hearing loss, dyslipidemia, and worsening hyperglycemia despite lifestyle interventions. Due to accelerated weight gain and declining glycemic control, dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was initiated. Over 48 weeks, BMI decreased from 190% to 160% of the 95th percentile, with a 0.95 z-score reduction, 1.2% HbA1c decrease into the normal range. This case expands our understanding of the ALMS1 mutational spectrum and provides the first longitudinal report of GLP-1 RA benefit in AS, supporting its consideration as adjunctive therapy and highlighting the need for further study.

Cantú syndrome (CS) is a rare genetic condition caused by pathogenic variants in either ABCC9 or KCNJ8, leading to gain-of-function of K_ATP-channels. The main clinical features are hypertrichosis and cardiovascular abnormalities. This study investigates the voice characteristics in individuals with CS, an aspect that has received little attention in previous research. A total of 18 participants with molecular genetically confirmed CS were recruited, 11 females and 7 males, aged 9-63 years. Voice pitch analysis was conducted using the Voice Tools application, comparing these findings with normative data from healthy individuals. We show that adult females with CS exhibit voice pitches consistently lower than the normative values, particularly below the bottom quartile, suggesting a distinct impact of the underlying gene defect on the adult female voice phenotype. Conversely, adult males with CS show less noticeable deviations in voice pitch compared to healthy males. Children with CS exhibit a voice pitch closer to normative ranges. Adults with CS exhibit a lower voice pitch than healthy controls, especially evident in females. This study highlights the influence of CS on voice pitch, possibly influenced by anatomical abnormalities in CS such as enlarged craniofacial structures and connective tissue alterations affecting vocal fold mass and pliability.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), caused by FOXL2 variants, has been divided into two subtypes by eyelid abnormalities with (BPES-I) or without (BPES-II) primary ovarian insufficiency (POI). This study investigated the genetic and phenotypic characteristics of FOXL2-associated BPES and their genotype-phenotype correlations. FOXL2 variants were identified by in-house next-generation sequencing and compared with public databases. Clinical features were also summarized. Eleven FOXL2 variants, including four novel, were detected in 11 families from our cohort. Based on literature, 273 FOXL2 pathogenic/likely pathogenic variants were reviewed in 650 patients from 548 families. Nearly half (47.6%, 130/273) of the variants were truncation. The most frequent (24.0%, 132/549) variant was p.A225_A234dup. In the polyalanine tract, variants leading to the deletion of 1-10 or expansion/insertion of 2 alanine residues were likely benign, whereas variants causing the expansion/insertion of 10-15 alanine residues were pathogenic. The proportion of truncation variants was significantly higher in patients with BPES-I (73.8%, 48/65) than in those with BPES-II (19.6%, 19/97). In conclusion, the pathogenicity of in-frame variants within the polyalanine tract was associated with the number of polyalanine residues. Truncation variants were frequently linked to the severe phenotype (BPES-I), highlighting their potential value in clinical diagnosis and patient management, particularly for preventing or treating POI.