Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands.

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin-1 or -2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.

TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature.

You-Hoover-Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow-up data on four previously reported individuals with YHFS.

The diagnostic odyssey of a patient with dihydropyrimidinase deficiency: a case report and review of the literature.

Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants of DPYS Patients with DHP deficiency exhibit a broad spectrum of phenotypes, ranging from severe neurological and gastrointestinal involvement to cases with no apparent symptoms. The biochemical diagnosis of DHP deficiency is based on the detection of a significant amount of dihydropyrimidines in urine, plasma, and cerebrospinal fluid samples. Molecular genetic testing, specifically the identification of biallelic pathogenic variants in DPYS, has proven instrumental in confirming the diagnosis and facilitating family studies. This case study documents the diagnostic journey of an 18-yr-old patient with DHP deficiency, highlighting features at the severe end of the clinical spectrum. Notably, our patient exhibited previously unreported skeletal features that positively responded to bisphosphonate treatment, contributing valuable insights to the clinical characterization of DHP deficiency. Additionally, a novel DPYS variant was identified and confirmed pathogenicity through metabolic testing, further expanding the variant spectrum of the gene. Our case emphasizes the importance of a comprehensive diagnostic approach using genetic sequencing and metabolic testing for accurate diagnosis.

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate.

Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts.We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P.We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1.This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature.

The FAR1-related phenotypes caused by the FAR1 gene encodes the peroxisomal protein fatty acyl-CoA reductase 1 (FAR1), which is required to reduce fatty acids to fatty alcohols used to form ether-linked alkyl bonds. Biallelic loss-of-function variants have been associated with severe psychomotor developmental delay, seizures, cataracts, growth retardation with microcephaly, and spasticity. However, heterozygous variants in FAR1 have been recently linked to a rare genetic disorder called cataracts, spastic paraparesis, and speech delay (CSPSD). Here, we present the first Middle Eastern patient with a de novo pathogenic heterozygous variant in FAR1 identified by exome sequencing (ES) analysis and a detailed overview of the reported clinical phenotypes and genotypes. Our patient represents the milder end of the clinical spectrum, with medication-free seizures by the first year of life, proper speech and fine motor development, as well as an absence of other previously reported features such as learning difficulties, axial hypotonia, and joint contracture. In addition, she had developmental dysplasia of the hip (DDH) that failed medical management, as well as faltering growth. Our patient adds to the small number of patients recognized to date and expands the clinical spectrum to provide better clinical delineation, improve diagnosis, and develop precision medicine approaches for this disorder.

ALG8-CDG: Molecular and phenotypic expansion suggests clinical management guidelines.

Congenital disorders of glycosylation are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid glycan biosynthesis. These disorders mostly manifest with multisystem involvement. Individuals with ALG8-CDG commonly present with hypotonia, protein-losing enteropathy, and hepatic involvement. Here, we describe seven unreported individuals diagnosed with ALG8-CDG based on biochemical and molecular testing and we identify nine novel variants in ALG8, bringing the total to 26 individuals with ALG8-CDG in the medical literature. In addition to the typical multisystem involvement documented in ALG8-CDG, our cohort includes the two oldest patients reported and further expands the phenotype of ALG8-CDG to include stable intellectual disability, autism spectrum disorder and other neuropsychiatric symptoms. We further expand the clinical features in a variety of organ systems including ocular, musculoskeletal, dermatologic, endocrine, and cardiac abnormalities and suggest a comprehensive evaluation and monitoring strategy to improve clinical management.