Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants.

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience.

OBJECTIVES: To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois. STUDY DESIGN: Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. RESULTS: One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. CONCLUSIONS: Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.

Continuous Venovenous Hemodialysis Via Extracorporeal Membrane Oxygenation Pump for Treatment of Hyperammonemia Secondary to Propionic Acidemia in Monochorionic Diamniotic Twin Boys.

Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 days of age. Continuous venovenous hemodialysis was performed successfully for both infants via extracorporeal membrane oxygenation pump, and both rapidly improved. They were taken off continuous venovenous hemodialysis and extracorporeal membrane oxygenation and discharged with dietary therapy. At 3 years of age, neurodevelopment showed globally delayed milestones.

Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

Fabry disease in infancy and early childhood: a systematic literature review.

PURPOSE: Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood. METHODS: A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age. RESULTS: The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age. CONCLUSION: This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated.

Reported communication ability of persons with trisomy 18 and trisomy 13.

OBJECTIVE: The aim of this study was to describe the communication ability of individuals with trisomy 18 and trisomy 13 syndromes. METHODS: Parents reported on children's potential communication acts, words, spontaneous gesture, and augmentative and alternative communication (AAC) using a parent report inventory (n = 32; age range 3-35 years). Potential communicative acts are defined as behaviors produced by an individual that may be interpreted by others to serve communicative functions. RESULTS: Potential communicative acts categorized as body movement displayed the highest median rank for reported occurrence followed by vocalization and facial expression. Although symbolic forms were ranked lower, more than half of the parents (66%) reported that their children produced at least one word, gesture or AAC form. Challenging behaviors or stereotypic movement displayed lowest median ranks. CONCLUSIONS: Results are discussed in terms of communication potential and the need to address AAC in trisomy 18 and 13.

Deletion and duplication of 15q24: molecular mechanisms and potential modification by additional copy number variants.

PURPOSE: To investigate the potential influence of additional copy number variants in patients with 15q24 rearrangements and the possible underlying mechanisms for these rearrangements. METHODS: Oligonucleotide-based chromosomal microarray analyses were performed, and the results were subsequently confirmed by fluorescence in situ hybridization analyses. Long-range polymerase chain reaction amplification and DNA sequencing analysis were used for breakpoint junction sequencing. RESULTS: We describe a 15-year-old boy with cognitive impairment and dysmorphic features with deletions in 15q24 and 3q21, a 2-month-old female infant with growth deficiency, heterotaxy, cardiovascular malformations, intestinal atresia, and duplications in 15q24 and 16q22, and a 3.5-year-old boy with developmental delay, microcephaly, and dysmorphic features, with duplications in 15q24 and 2q36.3q37.1. Breakpoint sequencing for the 15q24 deletion in the first patient revealed microhomology and suggested the underlying mechanism of either nonhomologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. CONCLUSIONS: The three described patients with 15q24 rearrangements have copy number variants at other loci and exhibit additional clinical features with a more severe phenotype than that observed in previously reported patients with isolated 15q24 rearrangements, suggesting that the genomic mutational load may contribute to the phenotypic severity and variability in patients with 15q24 rearrangements.