Molecular Modeling and Phenotypic Description of a Patient with a Novel Exonic Deletion of GALNS with Resultant Morquio Syndrome with Two Successful Pregnancies.

In this report, we describe phenotypic features of a patient with mucopolysaccharidosis type IVA (Morquio syndrome) harboring a novel exon 1 deletion in GALNS with enzymatic confirmation consistent with Morquio syndrome. To our knowledge, this is the first reported case of this variant. Additionally, we protein modelled wild-type GALNS and the pathogenic variant with an exon 1 deletion for comparative analysis using statistical mechanics methods described herein. We demonstrate that, even when the protein is translated, the mutation would affect protein stability and function via homodimer interaction modifications. Lastly, given the patient's 2 successful pregnancies, data about the management of pregnancies in mucopolysaccharidoses are reviewed, and we discuss the management of pregnancy in patients with Morquio syndrome.

A patient with a novel pathogenic variant in COL5A1 exhibiting prominent vascular and cardiac features.

The Ehlers-Danlos Syndromes (EDS) are a group of inherited connective tissue disorders with a worldwide prevalence of 1 in 2500 to 1 in 5000 births irrespective of sex or ethnicity. Fourteen subtypes of Ehlers-Danlos Syndrome (EDS) have been described, each with characteristic phenotypes and associated genes. Pathogenic variants in COL5A1 and COL5A2 cause the classical EDS subtypes. Pathogenic variants in COL3A1 cause vascular EDS. In this case report, we describe a patient with a phenotype resembling that of vascular EDS, caused by a novel pathogenic variant in COL5A1.

Application of the community dialogues method to identify ethical values and priorities related to pharmacogenomics.

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

Clinical description & molecular modeling of novel MAX pathogenic variant causing pheochromocytoma in family, supports paternal parent-of-origin effect.

The titular member of the MAX network of proteins, MYC-associated factor X (MAX), serves an important regulatory function in transcription of E-box genes associated with cell proliferation, differentiation, and apoptosis. Wild type MAX dimerizes with both MYC and MAD, both of which are members of the MAX network, and can promote or repress cell functions as needed. However, pathogenic variants in MAX are known to upset this balance, leading to uncontrolled oncogenic activity and disease phenotypes such as paragangliomas and pheochromocytomas. We report a 58-year-old male and his 32-year-old daughter, both of which have a history of pheochromocytoma and the unique nonsense MAX variant c.271C>T (p.Q91X). These individuals were diagnosed with pheochromocytomas in their early twenties that were later removed through corrective surgery. The father now presents with recurrent symptoms of hypertension, hyperhidrosis, and headaches, which accompany new pheochromocytomas of his remaining adrenal gland. Pathogenicity of this MAX variant is proven through molecular modeling. The case of this father-daughter pair supports both heritability of pheochromocytoma and the paternal parent-of-origin effect for MAX pathogenic variants.

Poirier-Bienvenu neurodevelopmental syndrome: A report of a patient with a pathogenic variant in CSNK2B with abnormal linear growth.

Casein kinase 2-related disorders have been linked to pathogenic variants in CSNK2A1 and CSNK2B. CSNK2B-related disease is predominantly associated with neurodevelopmental abnormalities affecting cognition; however, the extent of the phenotype associated with CSNK2B pathogenic variants is yet to be fully explored. Here, we describe a patient with features suggestive of Poirier-Bienvenu neurodevelopmental syndrome, harboring a novel CSNK2B pathogenic variant. We also report that the linear growth abnormalities could be a recurrent presentation in patients with this syndrome and suggest the effect of growth hormone therapy in our patient's stature.

Novel COL11A2 Pathogenic Variants in a Child with Autosomal Recessive Otospondylomegaepiphyseal Dysplasia: A Review of the Literature.

Otospondylomegaepiphyseal dysplasia (OSMED) is an inherited autosomal dominant and recessive skeletal dysplasia caused by both heterozygous and homozygous pathogenic variants in COL11A2 encoding the α2(XI) collagen chains, a part of type XI collagen. Here, we describe a 2-year-old girl presenting from birth with a phenotype suggestive of OSMED. On whole exome sequence analysis of the family via commercially available methods, we detected two novel heterozygous pathogenic variants in the proband. In addition, we reviewed the phenotype of autosomal recessive OSMED cases with COL11A2 pathogenic variants reported to date and quantitatively highlighted the phenotypic spectrum.

Novel Pathogenic Variant in the Cys110 Residue: A Genotype-Phenotype Report of a Patient with Norrie Disease.

Norrie disease is an X-linked genetic disorder caused by pathogenic mutations in the NDP . Here, we describe the clinical phenotype and genotype in a 19-week-old male infant with bilateral retinal detachment. Whole exome sequencing using available commercial methods on the proband revealed a hemizygous substitution in exon 3 of NDP , which suggests the etiology behind retinal detachment. This report not only adds to the expanding mutational spectrum of NDP -related retinopathies but also highlights the recurrence of pathogenic variants in the Cys110 residue, adding additional evidence to this residue as a potential mutational hot spot.

A Report of a Novel Pathogenic Variant in a Family with Buschke-Ollendorf Syndrome.

Buschke-Ollendorf Syndrome (BOS) is a benign autosomal dominant disorder caused by pathogenic mutations in LEMD3 . Here, we describe a family diagnosed to have varied phenotypes associated with BOS. Single gene testing of LEMD3 detected a heterozygous frameshift pathogenic variant in both the affected family members. Besides the phenotypic description, this report highlights the need for a comprehensive evaluation in connective tissue disorders and the importance of genotype-phenotype correlation in BOS.

Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia.

This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the CASR gene and a variant of uncertain significance in PDGFRB. The clinical phenotype is likely explained by the CASR variant, but we discuss how the PDGFRB variant could also participate in the phenotype.

Palpitations and Asthenia Associated with Venlafaxine in a CYP2D6 Poor Metabolizer and CYP2C19 Intermediate Metabolizer.

Cardiotoxicity has been extensively reported in venlafaxine (VEN) overdoses. Asthenia is also among the common side effects described for this antidepressant. VEN is metabolized mainly by CYP2D6 and to a minor extent by CYP2C19 to the major active metabolite O-desmethylvenlafaxine (ODV). Altered pharmacokinetic parameters in patients with polymorphisms in the CYP2D6 and CYP2C19 genes that result in decreased enzymatic activity have been documented. Here we describe a patient case of VEN associated palpitations and asthenia. The patient takes VEN extended release 150 mg twice daily. Genotyping confirmed the patient is a poor metabolizer for CYP2D6 and an intermediate metabolizer for CYP2C19. We propose that the palpitations and asthenia are related to sustained VEN exposure due to reduced metabolism.

Maple syrup urine disease: mechanisms and management.

Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex, which results in elevations of the branched-chain amino acids (BCAAs) in plasma, α-ketoacids in urine, and production of the pathognomonic disease marker, alloisoleucine. The disorder varies in severity and the clinical spectrum is quite broad with five recognized clinical variants that have no known association with genotype. The classic presentation occurs in the neonatal period with developmental delay, failure to thrive, feeding difficulties, and maple syrup odor in the cerumen and urine, and can lead to irreversible neurological complications, including stereotypical movements, metabolic decompensation, and death if left untreated. Treatment consists of dietary restriction of BCAAs and close metabolic monitoring. Clinical outcomes are generally good in patients where treatment is initiated early. Newborn screening for MSUD is now commonplace in the United States and is included on the Recommended Uniform Screening Panel (RUSP). We review this disorder including its presentation, screening and clinical diagnosis, treatment, and other relevant aspects pertaining to the care of patients.