Whilst biallelic variants in RTEL1 are an established cause of telomere biology disorder (TBD), the significance of heterozygous variants has been more challenging to establish. In this nationwide analysis, we describe 18 individuals with heterozygous pathogenic RTEL1 variants from seven families. All were identified during routine clinical genetic investigation for a variety of indications. Each family carried a different variant in RTEL1. Eight individuals had been diagnosed with a TBD-related disease (five with a hematological disorder, four with pulmonary fibrosis, overlap of one). No cases of clinically significant liver fibrosis had been detected. Cutaneous features of dyskeratosis congenita (abnormal skin pigmentation, oral leukoplakia, nail dysplasia and/or prematurely gray hair) were observed in four individuals. Telomere length (lymphocyte) was measured in nine individuals from six families and was below the 1st percentile in eight individuals. These cases illustrate the wide spectrum of disease and reduced penetrance associated with pathogenic RTEL1 variants, providing a real-world perspective on previous findings from research cohorts. We discuss the challenges surrounding incidental findings, clinical surveillance, and reproductive counseling in this context.

Translocation of newly synthesized proteins into the lumen of the endoplasmic reticulum (ER) is mediated by signal peptide recognition and cleavage. Here we report an individual with Simpson-Golabi-Behmel syndrome (SGBS) bearing a GPC3 missense variant at the signal peptide cleavage site of the glypican-3 protein. The c.71C>T; p.(Ala24Val) alteration in the key -1 position of the cleavage greatly reduces cleavage of the signal peptide, resulting in failure of the protein to efficiently exit the ER, and impaired glycosylation. Functional characterization of two other engineered variants at this position-one predicted to permit cleavage and the other to prevent it-corroborates our findings. This case highlights the potential for missense variants within the signal peptide cleavage site to underlie genetic disorders, and reinforces the idea that many of the missense variants in GPC3 that cause SGBS reside in motifs with high functional relevance to the processing and maturation of glypican-3.

Heterozygous de novo and inherited biallelic pathogenic variants in DNM1 have been reported in association with autosomal dominant (AD) and autosomal recessive (AR) developmental and epileptic encephalopathy, respectively, due to aberrant dynamin function or expression, with each inheritance pattern associated with a different mechanism of disease. We report an instance of DNM1-related early infantile developmental and epileptic encephalopathy due to compound heterozygous pathogenic variants with different functional effects: the de novo dominant negative-associated c.194C>A (p.Thr65Asn), and the maternally inherited loss of function-associated c.850C>T (p.Gln284*). We describe this patient's severe clinical presentation and disease progression as compared to those previously reported with either AD or AR DNM1-related disease. We hypothesize about the interactions and outcomes of the two variants at the molecular level following review of in vitro and in vivo functional data and demonstrate the utility of long-read genome sequencing for phasing the variants and confirming this individual's molecular diagnosis.

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that presents with severe chronic pain (CP) in adults. A limited number of NF1 research studies have evaluated behaviorally based interventions to address CP. The current study evaluated the efficacy of cognitive behavior therapy delivered via mobile application. The three-arm (treatment as usual [control], iCanCope only [iCC-NF], iCanCope + contingency management [iCC-NF + CM]) randomized clinical trial of 108 adults with NF1 and CP was completed during a 2-month intervention period. Significant improvements in pain interference (p = 0.005, d = 0.815) occurred in the iCC-NF + CM group when compared to the control group. Outcomes for pain self-efficacy (p = 0.009, d = 0.718), pain inflexibility (p = 0.026, d = 0.629), and chronic pain acceptance (p = 0.036, d = 0.653) significantly improved among the iCC-NF + CM group when compared to the control group. No significant differences were noted between iCC-NF + CM and iCC-NF. The current findings offer preliminary evidence of the added benefit of contingency management to mobile pain applications and provide an auxiliary treatment option for individuals with NF1. Trial Registration: ClinicalTrials.gov identifier: 2000029045.

Nance-Horan syndrome (NHS; OMIM 302350) is a rare, X-linked syndrome characterized by bilateral congenital cataracts leading to profound vision loss, specific dental anomalies including characteristic screwdriver blade-shaped incisors, facial anomalies, and intellectual disability. It is caused by deleterious loss of function variants or deletions involving the NHS gene at Xp22.13. Heterozygous females often present with similar, but less severe features than affected males. We describe a relatively large cohort of eight new patients with NHS, including two patients with microdeletions including NHS who had classical presentations, and provide detailed descriptions of the clinical findings for both affected males and females. The spectrum of clinical features in NHS is variable and can be mild, in particular for females, and the condition can remain undiagnosed. This report contributes to the delineation of the phenotypic and genotypic findings associated with this condition.

Copy number variants (CNV) are a major cause of neurodevelopmental disorders. Novel CNV syndromes may still be unrecognized. We report a 9q34.11 microduplication syndrome characterized by neurodevelopmental impairment and recurrent facial anomalies. Following the identification of a de novo 9q34.11 microduplication involving the SET and SPTAN1 genes in an 11-year-old girl with speech delay, intellectual disability, and behavioral abnormalities, we identified 13 additional patients with overlapping duplications. Besides the neurodevelopmental disorder, clinical features observed among affected individuals included recurrent dysmorphic features, such as midface hypoplasia and thin lips. The minimal region of overlap among these cases contained the SET gene, suggesting that its triplosensitivity may play a role in the observed phenotypes.

Elective genomic testing (EGT) for medically actionable disease predispositions may help adopted individuals (adoptees) with limited knowledge of family health history (FHH) information understand their inherited risks. In this prospective cohort study, patients who participated in Sanford Health's EGT program were surveyed at the time of enrollment between August 2020 and April 2022 about their motivations for pursuing EGT and perceived risks for three conditions. Data from self-reported adoptees and nonadoptees were analyzed using bivariate analyses. Of the 5799 eligible patients, 197 (3.4%) reported that they were adopted. Adoptees were more likely than nonadoptees to report lack of information about FHH as a very important motivation for pursuing EGT (81% vs. 32%, p < 0.001) and were more likely to rate it as their most important motivation (45% vs. 5%; p < 0.001). Other motivations, including learning about personal disease risk (72% vs. 61%; p = 0.016) and providing disease risk information to children (69% vs. 57%; p = 0.003), were also more likely to be rated as very important by adoptees than by nonadoptees, respectively. No differences in risk perceptions were observed. A lack of FHH information is an important reason why adoptees pursue EGT. Adoptees may hope that EGT will identify inherited risks for disease.

SLC30A9 mutations are linked to Birk-Landau-Perez syndrome, which is characterized by neurodevelopmental and renal disease, thought to result from impaired zinc homeostasis. In this report, we describe a patient with a homozygous likely pathogenic SLC30A9 variant with atypical chorio-retinal degeneration, suggesting retinal involvement in SLC30A9-associated diseases. The patient has bilateral sensorineural hearing loss, developmental delay, intellectual disability, abnormal balance, and Tourette syndrome. Ophthalmic manifestations include vascular attenuation, optic disc pallor, and pigmentation. In addition, the patient is noted to have high myopia. Our case highlights the importance of broad genetic testing in diagnosing rare multi-systemic disorders. Further research into the molecular mechanisms by which SLC30A9 results in photoreceptor disease is essential to understand its role in retinal degeneration and to develop potential therapeutic strategies.

Skeletal dysplasia (SD) encompasses over 700 heterogeneous genetic conditions affecting the development, growth and maintenance of the human skeleton. Challenges regarding feeding, nutrition, and physical activity are reported across the lifespan, but the lived experience of these issues is poorly understood. This study uses a qualitative mixed methodology to explore feeding, nutrition, and physical activity from the perspectives of individuals living with SD or their parents. Three semistructured focus groups were conducted in Norway and 13 interviews in Australia. The two qualitative datasets were thematically analyzed separately, and themes were then synthesized together. Thirty-five participants with SD or their parents participated across the two sites. Six major themes were identified: (i) early life feeding, development, and activity; (ii) managing energy intake and nutrition in older children and adults; (iii) practical considerations related to food preparation; (iv) weight gain; (v) holistic health care; and (vi) physical activity in older children and adults. Subthemes identified included breastfeeding challenges, inappropriate assessment of growth and nutritional status, barriers to being physically active in adulthood, and difficulty navigating food portions. Understanding the experiences of people with SD will support and inform future codesigned tailored solutions to address feeding, nutrition, and physical activity.

Smith-Kingsmore syndrome (SKS) is a rare autosomal dominant condition characterized by neurodevelopmental differences, macrocephaly/megalencephaly, describable facial features, sleep-wake abnormalities, hyperphagia, and overgrowth. SKS is caused by pathogenic gain-of-function variants in MTOR which lead to hyperactivation of the mTOR pathway. In this review, we discuss the history, epidemiology, molecular basis, clinical features, and management considerations for Smith-Kingsmore syndrome. In addition, we provide insight on early developmental milestones through a report on 14 individuals with a confirmed diagnosis of SKS. Among these individuals, 8/12 (67%) achieved crawling at an average age of 23 months, 9/14 (64%) achieved walking with an average age of 32 months, 5/9 (56%) achieved a pincer grasp at an average age of 23 months, 8/12 (67%) achieved the ability to use a device or utensil with an average age of 3.4 years, 10/13 (77%) achieved babbling at an average age of 20 months, 8/14 (57%) achieved their first word at an average age of 34 months, and 4/14 (29%) achieved the use of short phrases at an average age of 4.6 years. This review highlights advances in characterizing the natural history of SKS since it was first described 12 years ago and the need for additional research to inform genotype-phenotype correlations and targeted therapies to support individuals with SKS.

We report an 87-year-old female with a history of intellectual disability, severe speech impairment and behavioral issues. She was globally delayed in childhood. In adolescence, she had hallucinations, behavioral issues and was institutionalized. Her behavioral issues were treated, and her medical and behavioral course was stable until her 80's when she began to decline cognitively. She died at age 87. Exome sequencing revealed a novel predicted damaging missense variant (c.1913T>G; p.Met638Arg; NM_001136196.2) in the gene encoding Transportin-2 (TNPO2). Heterozygous variants in TNPO2 have been recently associated with an intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD; MIM:619556). Postmortem pathological examination of her brain revealed focal neuronal depletion in the dentate gyrus, CA1, and hilar regions of the hippocampus. These findings are consistent with human gene expression data showing normal to increased expression of TNPO2 in the dentate gyrus and CA1 region of the hippocampus. We suggest that the p.(Met638Arg) variant in TNPO2 is potentially disease-causing and associated with IDDHISD.

Craniosynostosis is characterized by premature fusion of cranial sutures, often with a complex genetic basis. While multiple genes have been implicated, the role of TGFBR3 mutations remains largely uncharacterized in human craniosynostosis. We report two Kuwaiti male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low-set ears, undescended testes, and developmental hip dysplasia. Duo whole exome sequencing research re-analysis identified a novel homozygous nonsense variant segregating with the phenotype in TGFBR3 (NM_003243.4: c.2418G>A, p.Trp806Ter), which encodes the betaglycan protein. Functional studies were performed to assess the pathogenicity of the variant. Expression of the mutant TGFBR3 in HEK293T cells demonstrated correct plasma membrane localization but revealed a truncated protein lacking its intracellular C-terminus. The mutant receptor retained canonical co-receptor function. In luciferase reporter assays, both wild-type and mutant TGFBR3 enhanced TGF-β1, TGF-β2, and TGF-β3 signaling. Mutant TGFBR3 produced an increase in luciferase activity relative to wild type only at the highest TGFβ1 concentration tested (10 pM). At lower TGFβ1 concentrations (0.1 and 1 pM) and across all concentrations of TGFβ2 and TGFβ3, mutant and wild-type receptors behaved similarly. This is the first report implicating a biallelic TGFBR3 nonsense variant in a syndromic, autosomal recessive form of craniosynostosis in a Middle Eastern population. The premature stop codon truncates the C-terminal region of the protein, perhaps disrupting critical regulatory or interaction domains. Our results suggest that dysregulated TGFβ signaling via the intracellular C-terminus of the protein may represent a novel pathogenic mechanism in cranial suture biology.

Neurometabolic diseases are a group of genetic disorders caused by defects in metabolic networks. To characterize the clinical, radiological, and molecular phenotype of three patients with variants in the NAXD gene, together with a review of the literature. A retrospective review of medical records was conducted. Three patients with chronic, progressive, recurrent encephalopathy triggered by fever were identified, with two clinically relevant variants in compound heterozygosity in the NAXD (NM_001242882.2) gene. Individuals 1 and 2: c.794_798dup and c.922C>T. Individual 3: c.269G>T and c.922C>T. We report three patients with neurometabolic disease characterized by recurrent progressive encephalopathy, developmental regression, and movement disorders, associated with systemic involvement and inflammatory-appearing central nervous system lesions due to NAXD enzymatic deficiency. The condition follows a febrile episode, often resulting in early mortality. Other cases showed recurrent episodes triggered by febrile events, characterized by encephalopathy, abnormal movements, ataxia, and seizures. The most frequent systemic manifestations included hematological, mucocutaneous, and cardiac involvement. These three patients broaden the clinical and molecular spectrum of NAXD-associated encephalopathy. Given its potential therapeutic implications, this condition should be considered in the differential diagnosis of neuroinflammatory diseases with poor outcomes, especially in cases with multisystem manifestations.

FRMPD4, a gene on the X-chromosome, encodes a neuronal scaffold protein, and six variants in this gene have been associated with X-linked neurodevelopmental disorder. We identified a novel intronic hemizygous variant (NM_014728.3:c.1198-6C>A) in FRMPD4 in a 2-year-old male patient with moderate developmental delay inherited from his asymptomatic heterozygous mother. Minigene assays in different cell lines demonstrated that this variant led to the consistent skipping of in-frame exon 12, which encodes 30 amino acids within the FERM domain. We speculated that this splicing defect may be due to the impaired recruitment of essential splicing factor U2AF2, as this C>A intronic variant is positioned at the center of the uridine-rich polypyrimidine tract, adjacent to the 3'-splice site. Structural modeling predicted that the loss of this region would disrupt the integrity of the FERM domain. Given that FRMPD4 mediates metabotropic glutamate receptor signaling via its FERM domain, we conclude that this intronic variant is likely pathogenic.

Spinal muscular atrophy with congenital bone fractures 2 is a rare and severe autosomal recessive neuromuscular disorder caused by pathogenic variants in ASCC1. This condition characterized by prenatal onset of severe hypotonia with fetal hypokinesia and congenital contractures results in arthrogryposis multiplex congenita, and increased incidence of prenatal fractures. To date, only truncating variants, loss of function and splicing variants have been described. Here, we report the first homozygous missense variant in ASCC1 identified prenatally in two full siblings with fetal akinesia deformation sequence. This variant affects a highly conserved residue within the RNA-ligase-like domain and leads to a nearly total absence of ASCC1 protein in muscle. This report broadens the knowledge on the pathogenesis of this disorder showing that missense variants should also be considered. It also highlights the importance of precise ultrasound examination combined with molecular genetic testing in the prenatal diagnosis of this severe neuromuscular disorder.

The World Health Organization defines health as "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." Medical interventions are often studied for effectiveness in carefully controlled clinical trials, but the parent-perceived, real-world helpfulness of medical management steps on health is less studied. As part of a broader study to create a valid, reliable health measure in DS, we surveyed caregivers of individuals aged 0-21 with Down syndrome (DS) about activities that were helpful for managing their children's health. From February 2023 to February 2024, we received 542 complete survey responses from a national sample. We present caregiver-reported information on actions that caregivers perceived as helpful to address medical conditions in individuals with DS, medical providers seen, and correlations with general health status. Caregiver reports revealed variable health management actions and diverse perceived helpfulness across health domains. Certain actions for constipation prevention and mental health management correlated with higher overall health scores. The utilization of primary care providers and specialists highlights the importance of interprofessional care and communication. Trial Registration: ClinicalTrials.gov: NCT04631237.

Neurofibromatosis 1 (NF1) is caused by pathogenic variants of the NF1 gene and increases the risk of tumor development. Phyllodes tumors are rare fibroepithelial neoplasms of the breast, for which the malignant forms exhibit high recurrence and metastasis rates. Herein, we report the case of a 19-year-old female with NF1 who developed a malignant phyllodes tumor of the breast. She noticed a breast mass 3 years before referral, which was diagnosed as a fibroadenoma. However, rapid tumor growth was observed 3 months prior to her hospital visit. Magnetic resonance imaging of the breast revealed a 9-cm tumor, and lumpectomy confirmed the malignancy. Recurrence necessitated a total mastectomy and pectoralis major resection. One year after surgery, metastases were detected in the left axillary lymph nodes and femoral head, requiring surgical intervention and denosumab treatment. No relapses were observed after 18 months. Comprehensive genomic profiling revealed a germline NF1 nonsense variant with loss of heterozygosity (LOH) in tumor cells. Additional somatic variants of TP53 and SMARCB1 have been identified. The TP53 variant is listed in the Catalogue of Somatic Variants in Cancer as a breast cancer-associated variant, whereas a splice site variant in SMARCB1 and LOH suggests a loss of SMARCB1 function. This case highlights the increased risk of malignancy in NF1 patients and underscores the need for comprehensive genomic profiling.

We describe a novel homozygous intragenic deletion in the ALS2 gene in an 8-year-old boy with Infantile-onset Ascending Hereditary Spastic Paraplegia (IAHSP) and oculomotor apraxia, thereby contributing to the expanding genetic landscape of ALS2-related disorders. Comprehensive neurological evaluation, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES) were performed. CMA revealed a run of homozygosity (ROH) at 2q33.1. WES identified a homozygous deletion encompassing exons 24-25 of ALS2, inherited from heterozygous parents. This clinical phenotype was consistent with the IAHSP spectrum, and no previous cases due to intragenic deletion have been reported. Our findings further expand the mutational spectrum of ALS2-related disorders and underscore the relevance of combining CMA and WES in the diagnostic workup of early-onset motor disorders, particularly in consanguineous families and unresolved cases. Greater awareness of rare intragenic deletions may improve early recognition and facilitate accurate genetic counseling in pediatric neurogenetics.

Autosomal recessive spinocerebellar ataxia type 20 (SCAR20) is a rare neurodevelopmental disorder caused by biallelic variants in the SNX14 gene and characterized by developmental delay, hypotonia, cerebellar atrophy, and hearing loss. This study aimed to characterize the clinical, radiological, and genetic presentation of affected individuals in a consanguineous Omani population. We conducted a retrospective and partly prospective case series involving 17 patients from seven consanguineous families seen at the Royal Hospital, Oman. Data were collected between September and November 2024, with historical assessments extending over the past decade. Clinical data were extracted from electronic records, and neuroimaging was reviewed. Whole exome sequencing of seven probands was performed, and familial segregation was confirmed through targeted Sanger sequencing. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines. The most common variant was SNX14 c.647_648del (p.Glu216Valfs24), identified in seven patients. Four patients carried the c.1132C>T (p.Arg378) variant, while two had a novel splice-site mutation, c.613-1G>A. One case involved a contiguous gene deletion affecting NT5E. Patient ages ranged from 1 month to 21 years. This report expands the mutational and clinical spectrum of SCAR20 in the Middle East and highlights the importance of early genetic testing, diagnostic vigilance, and multidisciplinary care in consanguineous populations.