Transient receptor potential vanilloid 1 (TRPV1) is a ligand and heat-gated ion channel expressed on nociceptors that plays a central role in thermal and chemical pain signaling. Loss-of-function variants in TRPV1 have been associated with reduced nociception. We report a 65-year-old woman with disabling polyneurofunctional/neuropathic symptomatology including migraine, functional gastrointestinal disorders, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Diagnostic evaluation revealed sensory polyneuropathy and autonomic instability. Whole genome sequencing reanalysis identified a heterozygous TRPV1 c.2174A > T (p.Lys725Met) Likely Pathogenic variant that is very rare and highly conserved. Our patient reports consistent, longstanding, marked hypersensitivity to heat, capsaicin, and alcohol, all of which are known TRPV1 agonists, supporting a gain-of-function mechanism for this variant. Furthermore, prior studies have implicated TRPV1 hyperactivity in migraine, nociceptive sensitization, and ME/CFS. Despite the excellent clinical correlation, causality of the variant cannot be definitively established without functional studies. This case expands the potential phenotypic spectrum associated with TRPV1, and highlights a possible role for TRPV1-mediated channelopathies in complex neurofunctional disorders including ME/CFS.
CHST3 ‐related skeletal dysplasia is a rare autosomal recessive skeletal disorder characterized by disproportionate short stature, progressive skeletal abnormalities, and congenital joint dislocations, typically with preserved cognitive function. We report a Syrian boy presenting with severe skeletal dysplasia, epilepsy, profound developmental delay, and intellectual disability. Clinical evaluation and trio exome sequencing identified a homozygous recurrent pathogenic variant in CHST3 and a de novo likely pathogenic splice‐site variant in GRIA3 . The skeletal manifestations, including the pattern of dysplasia, were consistent with CHST3 ‐related disease. However, the severity of the neurodevelopmental phenotype and epilepsy were not explained by CHST3 deficiency alone and were more consistent with a GRIA3 ‐related neurodevelopmental disorder. This case illustrates the importance of considering dual molecular diagnoses when a patient’s phenotype extends beyond the expected clinical spectrum of a known genetic condition. Furthermore, it provides additional evidence supporting the pathogenicity of a recurrent CHST3 variant observed in individuals of Syrian ancestry, suggesting a possible founder effect. Recognition of blended phenotypes resulting from multiple genetic diagnoses is essential to avoid inappropriate expansion of disease phenotypes and to ensure accurate genetic counseling and clinical management.
GATA2 haploinsufficiency is an autosomal dominant germline bone marrow disorder with heterogeneous manifestations, including cytopenias, recurrent infections, and progression to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Vascular complications, including venous thrombosis, are increasingly recognized. We present a male who developed extensive iliocaval thrombosis at age 16 after minor surgery and had persistent absolute monocytopenia, which remained unaddressed. He subsequently developed recurrent urogenital chlamydial infections and progressive cytopenias. Bone marrow evaluation revealed hypocellularity with dysmegakaryopoiesis and dysgranulopoiesis, consistent with hypocellular MDS; cytogenetics showed a gain of 1q with der(1; 21) (q10; q10). Comprehensive myeloid next-generation sequencing panel (that included GATA2) identified truncating STAG2, but no GATA2 coding mutations. Hereditary bone marrow failure testing of blood and skin fibroblasts, however, revealed a GATA2 intron 4 enhancer (+9.5Kb) variant, confirming GATA2 deficiency. He was referred for allogeneic hematopoietic stem cell transplant. During the pretransplant phase, anticoagulation was temporarily held for 3 days for central venous catheter placement, which resulted in renal infarction, indicating his ongoing high risk of thrombosis. This case highlights missed opportunities to diagnose GATA2 deficiency: the presence of persistent monocytopenia and the development of extensive venous thrombosis in an adolescent following minor surgery. In addition, it demonstrates the limitations of standard somatic exome-focused (‘myeloid disorder’) panels in detecting noncoding GATA2 germline variants. In addition, for patients on anticoagulation with a history of extensive thrombosis or considered to be at high risk of recurrent thrombosis, periprocedural bridging should be considered, after careful assessment of thrombotic and bleeding risks. Early recognition of GATA2 deficiency enables timely genetic confirmation, cascade testing of family members and risk-adapted strategies to prevent progression to AML, recurrent thrombosis, and infections.
Dyshormonogenesis accounts for 15%–20% of permanent congenital hypothyroidism (CH), and pathogenic variants in the thyroid peroxidase (TPO) gene are its most frequent cause. We report three brothers, all diagnosed with severe CH in the neonatal period and referred to our Medical Genetics Unit in 2021 for molecular characterization and genetic counseling. Whole‐exome sequencing, followed by a targeted thyroid gene panel, identified the same compound heterozygous TPO genotype in all three: NM_000547.6:c.1297G > A, p.(Val433Met), inherited from the carrier mother, and NM_000547.6:c.1964G > C, p.(Cys655Ser), inherited from the carrier father, confirming autosomal recessive dyshormonogenetic CH. At neonatal diagnosis, initial TSH exceeded 100 mIU/L in all three brothers (reference range approximately 1–20 mIU/L beyond the first days of life (Wassner 2018 and Léger et al. 2014)). Despite this identical genetic cause and comparable neonatal severity, the three brothers (hereafter Patient 1, Patient 2, and Patient 3, the index case) went on to show markedly divergent clinical trajectories. Patient 1 was treated continuously from birth. Patient 2 was correctly identified neonatally through a proactive family thyroid screening, prompted by his elder brother’s pre‐existing diagnosis, but was then lost to adequate endocrine follow‐up: his levothyroxine dose stayed static and unadjusted for several years while his TSH remained persistently elevated. Patient 3, the index case, was diagnosed at Day 3 through Guthrie neonatal screening, and it was his diagnosis that prompted the family‐wide reassessment which ultimately confirmed the genotype in all three brothers. He additionally carries a heterozygous SLC26A4 variant of uncertain significance. Together, these three cases show that the prognosis of treated neonatal CH depends as much on the quality of postdiagnosis monitoring as on how quickly the initial diagnosis is made. They also make the case for systematic family thyroid screening once a sibling is known to carry dyshormonogenetic CH, and for the value molecular diagnosis adds to parental counseling and reproductive planning.
Background 3q29 deletion syndrome (MIM #609425) is a rare genomic disorder characterized by variable expressivity and incomplete penetrance. Somatic mosaicism for a 3q29 deletion in an affected proband has rarely been documented. Mosaicism inferred from attenuation of the array signal requires confirmation by an independent method. When a chromosomal deletion encompasses an autosomal recessive (AR) disease gene, evaluation of the second allele may be informative. Extreme food selectivity associated with autism spectrum disorder (ASD) poses substantial but underrecognized nutritional risk. Case Presentation An 8‐year‐old Japanese boy with ASD, intellectual disability, absent speech, progressive obesity, hepatosplenomegaly, and congenital toe syndactyly underwent chromosomal microarray analysis (CMA). A 1.27‐Mb interval at 3q29 (arr[GRCh37] chr3:195,804,728–197,074,949) was segmented with a mean log2 ratio of −0.252 across 59 informative probes, against an excellent array quality (derivative log ratio spread 0.179). The signal returned to baseline immediately outside the interval. The magnitude of the attenuation is intermediate between a normal diploid state and that expected for a constitutional heterozygous deletion and is compatible with a suspected mosaic deletion; the laboratory’s automated nomenclature nevertheless assigned a copy number of 2, with the explicit caveat that copy number was not verified, and no independent confirmatory method was applied. The interval is atypical and nested within the recurrent 3q29 region and encompasses TFRC , RNF168 , PAK2 , and DLG1 . A targeted 15‐gene DNA repair panel identified no pathogenic or likely pathogenic variant on the second RNF168 allele. An incidental heterozygous NBN variant of uncertain significance (c.265A > G, p.Ile89Val; NM_002485.5) was nondiagnostic and did not alter management. Neither exome nor genome sequencing was available as a reimbursed clinical investigation, and parental samples were not obtained. Microcytosis and hypochromia were present at both time points; serum iron was within the reference interval at baseline and low at follow‐up, ferritin remained within the reference interval throughout, and no threshold‐based criterion for iron deficiency was met. Low 25‐hydroxyvitamin D, low vitamin C, and low retinol‐binding protein were documented at two time points and considered most likely related to the markedly restricted diet. Plasma amino acids; serum carnitine fractions; zinc; selenium; vitamins B1, B2, and B12; immunoglobulins; and alpha‐fetoprotein were unremarkable; serum copper was elevated in the presence of a raised C‐reactive protein, and ceruloplasmin was not measured. The cause of the hepatosplenomegaly remained unresolved. Conclusion An attenuated CMA signal at 3q29, compatible with a suspected mosaic deletion but not independently confirmed, was identified in a patient whose phenotype overlaps 3q29 deletion syndrome. Where a deletion encompasses an AR disease gene whose phenotype overlaps the presentation, second‐allele evaluation may add diagnostic resolution. This case highlights the importance of considering nutritional assessment in children with ASD and extreme food selectivity; the biochemical abnormalities persisted at follow‐up, although no vitamin D had been administered before the follow‐up sample and treatment exposure and adherence were not systematically documented.
