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We report three unrelated individuals with atypical clinical findings for cardio‐facio‐cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen‐activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non‐conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1‐related RASopathy. [ABSTRACT FROM AUTHOR]

In 2020, a new disease was reported by Polovitskaya et al., caused by a monoallelic, gain-of-function mutation in CLCN6, encoding the ClC-6 Cl−/H±exchanger. Here, we report the ophthalmic findings of one of the first three patients with this disease (the proband) and review the findings in the other two patients in the literature. The CLCN6 gene is part of the voltage-dependent chloride channel protein family. It functions as either a chloride channel aiding in cell-volume regulation and acidification of intracellular organelles or as an antiporter, which are membrane proteins involved in the transport of molecules across a phospholipid membrane. This particular gene is found in late endosomes. Ion transport across endosome membranes is essential for endosomal function. The proband carried a de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6. The patient reported herein has a notable optic nerve appearance. The nerve initially appeared elevated. Over time, the optic nerve elevation appearance decreased, associated with progressive vision loss with a visual acuity of 20/470 at last follow-up. While Clcn6−/− mice have been found to have a mild neuronal lysosomal storage phenotype, the three reported children with a de novo c.1658A>G (p.Tyr553Cys) variant displayed significant developmental delay and neurodegeneration. [ABSTRACT FROM AUTHOR]

Chromodomain helicase DNA‐binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole‐genome sequencing (WGS). We used a comprehensive clinical assessment, genome‐wide methylation analysis (GMA), reanalysis of WGS data, and CHD7 RNA studies to discover a novel variant that causes CHD7 haploinsufficiency. The 7‐year‐old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a CHD7‐associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of CHD7 detected a novel, de novo 15 base pair deletion in Intron 4 of CHD7 (c.2239‐20_2239‐6delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes CHD7 haploinsufficiency by disrupting the canonical 3′ splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel CHD7 variant that causes CHARGE syndrome. [ABSTRACT FROM AUTHOR]

Free sialic acid storage disorder (FSASD) is a rare autosomal recessive lysosomal storage disease caused by pathogenic SLC17A5 variants with variable disease severity. We performed a multidisciplinary evaluation of an adolescent female with suspected lysosomal storage disease and conducted comprehensive studies to uncover the molecular etiology. The proband exhibited intellectual disability, a storage disease gestalt, and mildly elevated urine free sialic acid levels. Skin electron micrographs showed prominent cytoplasmic vacuolation. Clinical exome and genome sequencing identified a maternally-inherited SLC17A5 variant: c.533delC;p.Thr178Asnfs*34. RNASeq of proband skin fibroblasts revealed exon 3 skipping, which was not detected in RNA from proband blood or parental fibroblasts. Targeted deep sequencing of proband fibroblast DNA revealed a 184 bp deletion in ∼15 % of reads, encompassing the 3' end of exon 3. Illumina Complete Long Read sequencing confirmed the deletion was in the paternally-inherited allele and found in a mosaic state in proband fibroblasts and muscle but not in blood or buccal cells. Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants. We report an adolescent female with atypical FSASD with tissue-specific mosaicism for an intragenic deletion in SLC17A5, explaining the atypical clinical course, mild biochemical abnormalities, and long diagnostic process., Competing Interests: Declaration of competing interest AS, TH, AC, KR, and AH were employed by Illumina Inc. at the time of this collaboration., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Patients with undiagnosed and/or rare disorders frequently manifest dysmorphic and neurological features. There is a lack of information on the effectiveness of telehealth in the evaluation of these disorders. We thus compared an unassisted virtual physical examination (PE) with an in-person PE in undiagnosed individuals and also assessed participant telehealth satisfaction. Twenty-six individuals enrolled in the Undiagnosed Diseases Network study underwent an in-home synchronous virtual PE, and a subsequent in-person PE, by the same clinician. The participants completed surveys on telehealth usability and provider empathy. On PE, general appearance and craniofacial features showed near perfect agreement (κ = 0.81-1.00) between the telehealth and in-person evaluations. Specific components of the neurological examination demonstrated substantial agreement (speech, gait, coordination; κ > 0.61), whereas others had moderate agreement (muscle tone, strength; κ = 0.41-0.60), and a few had none to slight agreement (skin; κ < 0.20). Some systems could not be examined in the virtual PE. Importantly, features relevant to diagnosis or management were missed on the virtual PE in only 2/26 individuals. The participants were satisfied with the quality of the telehealth interaction, as well as empathy demonstrated by providers in the virtual interface. Telehealth is effective for PEs in undiagnosed diseases and is acceptable to affected individuals., (© 2024 Wiley Periodicals LLC.)