Rossana Sanchez Russo

TOP3A ‐related mitochondrial disease is a rare autosomal recessive primary mitochondrial cytopathy caused by loss‐of‐function of the mitochondrial‐specific isoform of topoisomerase 3α, leading to multiple mitochondrial DNA deletions and mitochondrial DNA depletion. This condition has been associated with two different phenotypes. Very young patients present with severe growth faltering and early mortality, that is consistent with a Bloom syndrome‐like disorder. Adult‐onset chronic progressive external ophthalmoplegia, myopathy, and sensory ataxia, with rare hypertrophic cardiomyopathy (a MIRAS‐like phenotype), reflects a mitochondrial disorder. In this article, we expand the phenotype spectrum of TOP3A ‐related mitochondrial disease with a mitochondrial childhood onset form and present four previously unreported patients, including the outcomes of heart transplantation for three patients. Histopathological, electron microscopical, biochemical, and molecular characterization of muscle and heart tissue indicated mitochondrial dysfunction with combined complex deficiency associated with a mitochondrial DNA maintenance disorder primarily expressed in the heart. Heart transplantation was successful in patients with TOP3A ‐related mitochondrial disease that presented with cardiomyopathy in childhood, although there is slowly progressive neurological disease. In childhood, TOP3A ‐related disease presents with a combination of developmental delays, sensorineural hearing loss, cardiomyopathy with rhythm abnormalities, stroke‐like episodes, and Leigh‐like phenotype, and, in some, epilepsy. These mitochondrial phenotypes are different from the infantile Bloom‐like syndrome and the adult‐onset form.

Genotyping in patients with vascular malformations and/or somatic overgrowth guides precision treatment and is often required for insurance approval of targeted medications. Despite commonly accepted guidelines, uniform implementation of genetic testing in this population is hindered by practical challenges in the clinical setting. Here we compare the molecular diagnostic yield as a function of biopsy source, specifics of genetic testing, and type of insurance. We conducted a retrospective chart review of patients who had genetic testing performed at various commercial or academic laboratories on a biopsy for vascular malformations and/or somatic overgrowth. Diagnostic yield was compared by specimen type, depth of coverage (DOC), and billing method. 70 genetic tests were reviewed for 56 patients. High DOC testing yielded a significantly higher diagnostic rate of 74.3% compared to 20.0% in low DOC testing ( p < 0.001). Core biopsies (vs. skin punch) and tests utilizing private insurance/institutional billing (vs. Medicaid) also showed a higher diagnostic yield. In the clinical setting, patients reliant on low DOC commercial testing due to insurance barriers face significantly lower diagnostic rates, underscoring a clear inequity in diagnostic outcomes and demonstrating a need for improved testing access.

The CELSR1 gene is a core component of the tissue/planar cell polarity signaling pathway. It encodes a developmentally regulated protein that belongs to the adhesion G protein-coupled receptors. Herein we describe seven subjects, from five unrelated families, featuring a neurodevelopmental disorder associated with biallelic CELSR1 variants. The main phenotypic features of this disorder are different types of brain malformations (including pachygyria, periventricular nodular heterotopia, abnormal corpus callosum, white matter abnormalities, hypoplasia of brainstem and cerebellum), variable degrees of neurodevelopmental delay and intellectual disability, behavioral disorders, and, in some subjects, epilepsy. Using whole exome sequencing, we identify five compound heterozygous variants and one homozygous variant of CELSR1 in these subjects. We infer the pathogenicity and functional effects of these variants through bioinformatic analysis, protein modelling and prediction tools. To further characterize the effects of mutant CELSR1, we generate Celsr1 knockout mice, which exhibit partial agenesis of the corpus callosum, periventricular heterotopia and irregular shape of the ventricular/subventricular zone, enlarged lateral ventricles with a fully penetrant phenotype, and increased susceptibility to seizures. These findings emphasize the importance of CELSR1 in several polarity-dependent processes during embryonic and postnatal development.

Early diagnosis by newborn screening (NBS) has contributed to improved outcomes in children with cystic fibrosis (CwCF). Georgia’s two-tiered algorithm consists of a fixed immunoreactive trypsinogen (IRT) cut-off followed by a 39-variant CFTR genetic panel. We conducted a retrospective review of CwCF born in Georgia from 2007 to 2022 to evaluate false negative NBS frequency. We characterized CwCF whose diagnosis was delayed beyond 28 days of age despite positive NBS. Six cases were detailed demonstrating the impact of missed and delayed diagnoses. We examined IRT trends from 2018 to 2022 and cut-off approaches. Missed case detection by expanded CFTR variant assays was assessed. Of 390 CwCF born in Georgia, 18 (4.6%) had false negative NBS—6 due to lack of CFTR variant detection and 12 due to low IRT values. Thirty children had delayed diagnosis, with the majority related to sweat testing. Minoritized children made up 19% of the population but 43% of missed and 44% of delayed diagnoses. Black and Hispanic infants had higher odds of missed or delayed diagnosis compared to non-Hispanic White infants (OR = 2.7, p = 0.027 and OR = 6.1, p < 0.001, respectively). Average IRT values varied across kits and were lower in warmer seasons. Expanded CFTR assays would reduce missed cases. Our results informed recommendations for improvement at multiple steps in the NBS process.

Cystic fibrosis (CF) newborn screening (NBS) aims to improve outcomes through early diagnosis, yet disparities in time to diagnosis remain. This study examines CFTR allele frequencies and variant panel performance among a diverse CF population in Georgia to inform recommendations for updating the NBS algorithm and improving equity. This cross-sectional study includes 969 people with CF (PwCF) from Georgia’s accredited CF centers. CFTR variant frequencies were calculated according to race and ethnicity. Panel performance was evaluated for Georgia’s current Luminex-39 variant test and three expanded panels. Statistical analyses compared detection rates across panels and demographic groups. Georgia’s diverse CF population demonstrates a unique CFTR allelic variability compared to national data. Increasing panel size enhances case identification. A panel including 719 CF-causing variants from the CFTR2 database significantly improves case detection from 93% to 97% (p = 0.002), as well as two-variant detection from 69% to 86% (p < 0.001). Detection of minoritized PwCF also improves with increasing panel size. However, even using the 719-variant panel, detection of non-Hispanic Black PwCF remains significantly lower compared to non-Hispanic White PwCF (case detection: p = 0.003; two-variant detection: p < 0.001). In conclusion, the use of expanded CFTR panels for NBS in Georgia would enhance timely diagnosis and improve equity.

Arginase 1 deficiency (ARG1‐D) is an autosomal recessive urea cycle disorder characterised by chronic hyperargininaemia, progressive spasticity, loss of mobility, and cognitive dysfunction. Standard of care (SOC), based on dietary protein restriction, rarely prevents progression. Pegzilarginase, a recombinant human enzyme, is the first approved disease‐modifying therapy. We report outcomes from Study 102A (n = 14; up to 5 years) and the PEACE long‐term extension (LTE) (n = 31; up to 3 years). Weekly pegzilarginase was administered with SOC. Outcomes included functional mobility (2‐/6‐minute walk tests [2MWT/6MWT], Gross Motor Function Measure [GMFM] D/E), spasticity (Modified Ashworth Scale [MAS]), plasma arginine, guanidino compounds, and safety. In PEACE, LTE arms were named according to initial 24‐week double‐blind treatment: placebo–pegzilarginase or pegzilarginase–pegzilarginase. Of 39 evaluable participants, 37 (95%) met composite response or achieved maximum score in ≥ 1 motor function domain. In 102A, mean 6MWT improved to 68.2 m (+19%; n = 12); GMFM‐D/E increased by 2.7/3.7. In PEACE (pegzilarginase–pegzilarginase; placebo–pegzilarginase), 2MWT improved to 16.5 m (+25%; n = 6) and 13.5 m (+16%; n = 2); GMFM‐D/E improved by 4.3/6.0 (n = 6) and 5.3/11.3 (n = 3). Spasticity improved in 21/25 (84%), with 12 reaching MAS 0 (no spasticity). Pegzilarginase sustained plasma arginine control: in 102A, means were 118 μmol/L at Week 192 (n = 9); in PEACE, < 115 μmol/L through Week 96 (n = 11). Guanidinoacetic acid normalised; N‐acetylarginine approached normal; argininic acid and α‐keto‐δ‐guanidinovaleric acid declined by > 50%. Most adverse events were mild/moderate; no treatment‐related discontinuations or persistent antibodies occurred. Pegzilarginase produced sustained improvements in mobility, spasticity and biochemical control, supporting early intervention, long‐term use and disease modification in ARG1‐D.

3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next‐generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC‐ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC‐ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next‐generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.