Lessons learned from 5 years of pegvaliase in US clinics: A case series.

Objective: To provide insights and strategies for pegvaliase management in challenging cases with phenylketonuria (PKU) based on the first 5 years of experience with pegvaliase in real-world clinical practice.

Methods: Twelve PKU experts gathered during a one-day, in-person meeting to discuss clinical cases illustrating important lessons from their experiences treating patients with pegvaliase in real-world clinical practice. Challenges with pegvaliase experienced prior to and during treatment and corresponding strategies to overcome them were discussed.

Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

Background: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU.

The smallest likely pathogenic duplication of a SOX9 enhancer identified to date in a family with 46,XX testicular differences of sex development.

Copy number variants that duplicate distal upstream enhancer elements of the SOX9 gene cause 46,XX testicular differences of sex development (DSD) which is characterized by a 46,XX karyotype in an individual presenting with either ambiguous genitalia or genitalia with varying degrees of virilization, including those resembling typical male genitalia. Reported duplications in this region range in size from 24 to 780 kilobases (kb). Here we report a family with two affected individuals, the proband and his maternal uncle, harboring a 3.

The State of Newborn Screening in South Dakota.

South Dakota's Newborn Screening (NBS) program has been in existence for nearly 50 years. What began as a screen for a single condition has now expanded to more than 50 conditions. From 2005-2019 alone, 315 infants were confirmed as positive for a condition detected by the newborn screen in South Dakota.

Individual with Homozygous TECR Variant Expands Upon the Existing Phenotype for a Hutterite Founder Mutation.

Intellectual disability (ID) is ubiquitous across nations affecting roughly 1 percent of the world's population. Improvements in genetic testing methodologies have led to increased understanding about the etiology of ID. However, many cases remain idiopathic.

Novel variants identified in in two siblings with Filippi syndrome.

Pathogenic variants in have previously been reported in Filippi syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than 10 patients with pathogenic variants in associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine), and all but one have been homozygous for a pathogenic variant.

Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing.

RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein.

Jumonji domain containing 1C (JMJD1C) sequence variants in seven patients with autism spectrum disorder, intellectual disability and seizures.

The Jumonji domain containing 1C (JMJD1C) gene encodes the Jumonji domain-containing protein 1C (JMJD1C) and is a member of the jmJC domain-containing protein family involved in histone demethylation that is expressed in the brain. We report seven, unrelated patients with developmental delays or intellectual disability and heterozygous, de novo sequence variants in JMJD1C. All patients had developmental delays, but there were no consistent additional findings.

GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder.

Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND).

Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex.

Case Report of Infant With Features of Beckwith-Wiedemann Syndrome Diagnosed With Genome-wide Uniparental Disomy.

Uniparental disomy (UPD), where two copies of genetic material are from one parent, and none from the other, is a familiar cause of imprinting. We present a premature infant with organomegaly and congenital hyperinsulinism found to have complete UPD of paternal origin as determined by Mendelian inheritance error analysis.

An Exploration of Genetic Test Utilization, Genetic Counseling, and Consanguinity within the Inborn Errors of Metabolism Collaborative (IBEMC).

The Inborn Errors of Metabolism Collaborative (IBEMC) includes clinicians from 29 institutions collecting data to enhance understanding of metabolic conditions diagnosable by newborn screening. Data collected includes hospitalizations, test results, services, and long-term outcomes. Through evaluation of this data, we sought to determine how frequently genetic counseling had been provided, how often genetic testing was performed, and also determine the consanguinity rate in this population.

Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.

Keppen-Lubinsky syndrome (KPLBS) is a rare disease mainly characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, a narrow nasal bridge, a tented upper lip, a high palate, an open mouth, tightly adherent skin, an aged appearance, and severe generalized lipodystrophy. We sequenced the exomes of three unrelated individuals affected by KPLBS and found de novo heterozygous mutations in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel and maps to the Down syndrome critical region between DIRK1A and DSCR4. In particular, two individuals shared an in-frame heterozygous deletion of three nucleotides (c.

Identification of a founder mutation for maple syrup urine disease in Hutterites.

Maple syrup urine disease (MSUD) is an organic acidemia detected on newborn screening. The condition has been reported with increased frequency in certain founder populations including Hutterites. We present a case of MSUD in a Hutterite boy.

Congenital nasal pyriform aperture stenosis and ocular albinism co-occurring in a sibship with a maternally-inherited 97 kb Xp22.2 microdeletion.

Congenital Nasal Pyriform Aperture Stenosis (CNPAS) is a rare congenital malformation caused by overgrowth of the maxillary bone. We report on two patients, brothers born 3 and 1½ years apart, both presented at birth with radiographically diagnosed CNPAS. Both siblings also were born with ocular albinism, which is known to have X-linked inheritance.

Sani-cloth wipe mimics rare enzyme deficiency malonic aciduria on newborn screen.

Within a 7-month period at our institution, newborn screening by tandem mass spectrometry revealed 10 cases with elevated levels of malonylcarnitine, which suggested malonic aciduria. Malonic aciduria is a rare autosomal recessive inborn error of metabolism. Confirmatory testing yielded normal results in all the newborns involved.

Molecular mapping of the Edwards syndrome phenotype to two noncontiguous regions on chromosome 18.

In an effort to identify regions on chromosome 18 that may be critical in the appearance of the Edwards syndrome phenotype, we have analyzed six patients with partial duplication of chromosome 18. Four of the patients have duplications involving the distal half of 18q (18q21.1-qter) and are very mildly affected.