Autoinflammatory disorders (AIDs) are a clinically heterogeneous group of inborn errors of immunity primarily caused by dysregulation in the innate immune system. Clinical diagnosis is often challenging due to clinical heterogeneity and the overlapping phenotypes with other inborn errors of immunity and monogenic conditions that mimic AIDs. Worldwide, and especially in India, there is a lack of systematic large cohort studies employing genomic testing early in the course of evaluation for individuals with autoinflammatory disease. Herein, we describe our experience using exome sequencing as a first-tier investigation in evaluating 202 individuals from 196 unrelated families with possible monogenic AIDs. Consanguinity was noted in 19% of the families. Recurrent fever was the most common manifestation (90%), frequently associated with arthritis (54%), skin lesions (38%), hepatosplenomegaly (23%), oral ulcers (21%) and lymphadenopathy (21%). Exome sequencing could identify a molecular diagnosis in 50 of 196 (25%) families of whom 30 (60%) had variants in genes associated with monogenic AIDs, 10 (20%) had other distinct inborn errors of immunity and 10 (20%) had monogenic conditions with phenotypic overlap with AIDs. We identified 21 variants in genes associated with monogenic AIDs, of which 20 (95%) were single nucleotide variants and one (5%) was a copy number variant. Notably, seven (33%) of the 21 variants were novel. This study highlights the diagnostic challenges posed by phenotypic overlap in this group of disorders and demonstrates the utility of exome sequencing in enabling a timely diagnosis, including conditions that mimic AIDs thereby facilitating targeted therapy and genetic counseling.
Pathogenic variants in LZTR1 are an established cause of Noonan syndrome (NS) and uniquely exhibit both autosomal dominant (AD) and autosomal recessive (AR) inheritance. However, the phenotypic spectrum and genotype-phenotype correlations remain incompletely defined. We conducted a multi-center retrospective chart review of patients diagnosed with LZTR1-NS evaluated at three tertiary care centers. Clinical, molecular, and imaging data were systematically collected. A comprehensive literature review (2015-2025) identified 100 additional individuals meeting inclusion criteria. Comparative analyses were performed to evaluate phenotypic patterns by inheritance. Among 21 previously unreported patients aged 6 months to 49 years, 15 had AD NS and 6 had AR NS. Clinical features were largely consistent with prior reports, including high prevalence of craniofacial dysmorphism, neurodevelopmental and multisystem involvement. Cardiac manifestations were frequent, with pulmonary valve stenosis as the most common lesion. Hypertrophic cardiomyopathy appeared more prominent among AR NS. Notably, lymphatic abnormalities were observed at a higher frequency than previously reported. Compared to the literature, our cohort highlights novel findings, including the co-occurrence of AD LZTR1-NS with 22q11.2 deletion and two patients with AR NS with features suggestive of schwannomatosis. These findings expand the clinical spectrum of LZTR1-NS and have important implications for diagnosis, surveillance, and genetic counseling.
Vissers-Bodmer Syndrome (VIBOS) is a rare autosomal dominant neurodevelopmental disorder caused by variants in the CNOT1 gene. Affected individuals present with a broad clinical spectrum of developmental delays, intellectual disability, seizures, hypotonia, and behavioral challenges. Most affected individuals also have nonspecific dysmorphic facial features but no recognizable gestalt. We report a de novo pathogenic CNOT1 variant in a 6-month-old male patient who was evaluated for imperforate anus, partial agenesis of the corpus callosum, macrocephaly, hydronephrosis, overlapping toes, and fifth nail hypoplasia. Clinical trio exome sequencing identified a de novo heterozygous CNOT1 nonsense variant (c.4918C>T, p.(Arg1640*)) that has not been previously reported. The patient is now 3 years old and has no growth or developmental concerns in clinical follow-up. This case highlights a novel pathogenic CNOT1 variant and extends the clinical spectrum of VIBOS to include age-appropriate growth and neurodevelopment and the previously unreported presentation of imperforate anus. Recognition of these additional findings may facilitate earlier diagnosis and enhance understanding of the phenotypic variability associated with VIBOS.
Glycogen storage disease Type XV (GSD-XV; OMIM #613507) is an ultra-rare autosomal recessive disorder caused by biallelic pathogenic variants in GYG1, typically presenting with late-onset skeletal myopathy, while predominant cardiac involvement is exceptional. We report a 31-year-old man with chest pain, fatigue, and exertional dyspnea whose electrocardiogram demonstrated a spontaneous Type-1 Brugada pattern with complete right bundle branch block. Transthoracic echocardiography revealed nonobstructive left ventricular hypertrophy with preserved ejection fraction, whereas speckle-tracking showed markedly reduced global longitudinal strain with a heterogeneous distribution and absence of apical sparing. Cardiac magnetic resonance demonstrated mid-to-apical hypertrophy and patchy nonischemic late gadolinium enhancement consistent with myocardial fibrosis. Clinical exome sequencing identified a homozygous pathogenic GYG1 variant (NM_004130.4:c.304G>C; p.(Asp102His)) supported by functional evidence and familial segregation consistent with autosomal recessive inheritance. No pathogenic variants were detected in genes classically associated with Brugada syndrome, supporting a substrate-related Brugada phenocopy. Neurological examination, serum creatine kinase levels, and systemic evaluation were unremarkable. This case further expands the recognized cardiac phenotype associated with GYG1 deficiency by illustrating the coexistence of metabolic hypertrophic cardiomyopathy, myocardial fibrosis, and a Brugada phenocopy pattern, while highlighting a potential link between structural remodeling and arrhythmogenic electrical manifestations.
Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.
Schmid metaphyseal chondrodysplasia (SMCD, OMIM #156500) is a skeletal dysplasia characterized by progressive short stature, shortening of the tubular bones, and genu varum. In this study, we present the clinical and genetic findings of patients with COL10A1 variants. A total of seven patients from two unrelated families were included, comprising three children and four adults. The mean age was 6.1 years in children and 41.2 years in adults. Short stature was present in all patients except one, with height SDS ranging from -0.6 to -3.7. All patients exhibited genu varum. Radiographic evaluation revealed coxa vara, metaphyseal irregularities of the long bones, and platyspondyly in all patients; shortening of the tubular bones was observed in six patients, and femoral bowing in two patients. Wormian bones were identified in all six patients from Family 1, representing a previously unreported finding. Two patients underwent hemiepiphysiodesis for the treatment of genu varum. Based on the clinical features, SMCD was suspected in all patients. Genetic diagnosis was established using COL10A1 single-gene analysis in two index patients, and the identified variants were subsequently confirmed by Sanger sequencing in family members. In Family 1, a heterozygous likely pathogenic variant in COL10A1, NM_000493.4:c.1744T>G (p.Tyr582Asp), was identified. In Family 2, a homozygous likely pathogenic variant in COL10A1, NM_000493.4:c.1954C>T (p.Leu652Phe), was detected. Segregation analysis demonstrated heterozygosity for the variant in both clinically unaffected parents. Our findings expand the clinical spectrum of SMCD and underscore the importance of integrating clinical and radiographic evaluation with molecular genetic testing for accurate diagnosis. The identification of a homozygous COL10A1 variant in our patient provides additional support for previous reports demonstrating that SMCD can follow both autosomal dominant and autosomal recessive patterns of inheritance.
Rapid genomic testing (rGT) is increasingly being used as a first-tier test for critically ill individuals. Limited outcome data make ensuring appropriate utilization challenging. This study evaluates ordering trends and factors impacting the diagnostic yield of rGT. A retrospective analysis was performed on rGT orders reviewed between 2020 and 2024. Diagnostic yield, turnaround time (TAT), and clinical status at the time of the result were ascertained through chart review. Of 270 rGT orders, 98% (265/270) were ordered inpatient, and 79% (213/270) were rapid genome sequencing. While rGT utilization increased more than tenfold in the study period, the diagnostic yield declined. The overall diagnostic yield in our cohort was 20% (54/270). Only 10% (27/265) of inpatient cases were both diagnostic and resulted while the individual was still hospitalized. In 2024, the mean laboratory TAT was reduced to 8.6 days (n = 135) from the 2020-2023 average of 12.5 days (n = 135, p < 0.0001). Increased uptake of rGT as a first-tier genetic test suggests a shift toward broad inpatient genetic testing and is associated with a lower diagnostic yield over time. Evidence-based laboratory stewardship should seek to balance expanded access to rGT while maintaining high clinical utility.
CHARGE syndrome (OMIM #214800) is an autosomal dominant disorder caused by mutations in the CHD7 gene in most cases. Although originally defined by the CHARGE acronym (coloboma, heart defects, choanal atresia, growth restriction, genital hypoplasia, and ear anomalies), the recognized phenotype has expanded considerably to include highly prevalent manifestations such as cranial nerve dysfunction, vestibular anomalies, feeding and gastrointestinal complications, endocrine abnormalities, and musculoskeletal involvement. Skeletal abnormalities have been described previously; however, the frequency, spectrum, and clinical significance of spinal abnormalities remain incompletely characterized and are likely underrecognized. We conducted a retrospective review of 54 individuals with CHARGE syndrome to characterize spinal involvement and evaluate implications for management. Skeletal imaging was available in 40 of the 54, among whom abnormalities demonstrated considerable phenotypic heterogeneity, highlighting the importance of systematic musculoskeletal evaluation. Skeletal abnormalities were identified in 70% of individuals and included vertebral segmentation defects, intervertebral disc space narrowing, rib anomalies, and scoliosis. Scoliosis or kyphosis of any degree was present in 60% of the imaged individuals. Cervical spine involvement was identified in 43%. Two individuals (4%) were found to have os odontoideum, one of whom developed clinically significant atlantoaxial instability requiring surgical stabilization. Osteopenia was identified in 33% of individuals. Our findings further support previous reports demonstrating that spinal abnormalities are common in CHARGE syndrome while identifying os odontoideum as a previously unrecognized cervical spine manifestation with important clinical implications. Given that neuroimaging is frequently performed in CHARGE syndrome for evaluation of inner ear and cranial nerve abnormalities, careful assessment of the cervical spine during these studies may facilitate early recognition of clinically significant abnormalities without substantially increasing imaging burden. Our findings also emphasize the importance of longitudinal orthopedic surveillance, proactive bone health management beginning in childhood, and multidisciplinary care incorporating rehabilitation strategies to optimize long-term musculoskeletal outcomes.
Turner syndrome (TS) is associated with thoracic aortopathy and increased risk for aortic dissection, yet the natural history of aortic dilation is not well understood. We performed a retrospective longitudinal study of individuals with TS who participated in the TS Society of the United States Healthy Heart Project between 2003 and 2023. Participants were selected in descending rank order of aortic size index (ASI, > 18) or TS-specific Z-score (< 18) to generate a cohort intentionally enriched for the largest unoperated aortic diameters. Serial echocardiograms were re-measured using standardized techniques. Patient-specific growth rates were estimated using a pooled mixed-effects best-model framework and compared with the entire HHP longitudinal dataset to evaluate trajectories across risk strata. The primary endpoint was a composite of all-cause death, aortic surgery, or aortic dissection. Twenty-nine individuals (20 adults, 9 pediatric) were followed for a median of 13 years. Longitudinal aortic growth was generally slow (≤ 0.018 cm/year), with three rapid and seven mild progressors. No aortic dissections were observed. Clinical events were driven by elective aortic surgery and death. Height-indexed aortic diameter (aortic height index, AHI) demonstrated the strongest association with the composite endpoint, outperforming ASI and TS-specific Z-scores. In a TS cohort enriched for the largest unoperated aortas, baseline aortic size and clinical risk factors rather than growth rate primarily determined clinical outcomes. These findings support an integrated framework for aortic risk assessment in TS.
Achondroplasia is a skeletal dysplasia associated with severe short stature and multisystem complications due to a gain-of-function pathogenic variant in the FGFR3 gene. Vosoritide, a C-type natriuretic peptide analog, has demonstrated efficacy in clinical trials. The objective of this study was to describe the effectiveness, safety, treatment continuity, and caregiver-reported outcomes of vosoritide in routine practice across heterogeneous health systems in Latin America in a real-world context. We conducted a retrospective, multicenter, multinational cohort study including children with molecularly confirmed achondroplasia treated with vosoritide in centers from Argentina, Colombia, Uruguay, Mexico, and Chile. Eligible patients had ≥ 6 months of treatment and at least two anthropometric evaluations. Height, annualized growth velocity (AGV), body proportion measures, treatment interruptions, adverse events, and parent-reported outcomes were analyzed. Fifty-two patients (mean age 5.9 years at treatment initiation) were included, with a mean treatment duration of 539 days and high adherence (93.9% time without interruptions). Height Z-scores increased significantly from 6 to 36 months (0.33 to 1.58; p < 0.001 to p < 0.05). The most significant impact in AVG is observed during the first year of treatment with vosoritide, followed by a subsequent stabilization, reaching growth rates comparable to those of the healthy population. Increases were consistent across sexes and age groups. All patients were in a higher percentile range for AGV during treatment compared to before treatment, in some cases exceeding the 95th percentile, when compared to reference curves. Body proportion indices remained stable. All patients demonstrated gains in linear growth, although the magnitude of increase varied across individuals. Adverse events were frequent but mild, mainly injection-site reactions; no severe adverse events or treatment discontinuations due to safety issues occurred. Parent-reported outcomes were highly favorable, with 98% of caregivers perceiving positive changes in their children's overall well-being, daily functioning, or quality of life, and all caregivers expressing willingness to recommend the treatment. In real-world clinical practice across Latin America, vosoritide demonstrated rapid and sustained gains in linear growth, favorable tolerability, high adherence, and meaningful benefits as perceived by caregivers. These results reinforce the generalizability of vosoritide therapy in heterogeneous healthcare systems and highlight the relevance of real-world evidence for informing treatment decisions in rare diseases.
Pentalogy of Cantrell (POC) is a rare constellation of congenital differences characterized by a midline supraumbilical abdominal wall defect, lower sternal defect, deficiency of the anterior diaphragm, defect of the diaphragmatic pericardium, and congenital intracardiac anomalies. While its embryologic origins are presumed to stem from early developmental disruption, the underlying etiology remains poorly understood. To systematically map and characterize reported cases of pentalogy of Cantrell in the literature, with emphasis on clinical features, associated anomalies, genetic findings, and proposed developmental mechanisms. A scoping review of published cases of pentalogy of Cantrell was conducted using PubMed, with additional cases identified through reference lists of included articles. Eligible studies included published case reports and case series describing complete or incomplete pentalogy of Cantrell. Data were charted on study characteristics, phenotypic features, associated anomalies, genetic findings, and relevant perinatal and familial factors. In some instances, cases cited within secondary reports could not be independently verified due to lack of access to the original publications. A total of 242 cases of complete pentalogy of Cantrell and 441 cases of incomplete presentations were identified. Out of the 683 total cases, 91 cases included some form of genetic finding. Reported cases demonstrate substantial phenotypic variability, with frequent intracardiac anomalies and variable extracardiac findings. Classification was often limited by incomplete reporting, inconsistent diagnostic criteria, and restricted clinical detail. Genetic evaluations were inconsistently performed and no unifying etiology has been identified. In our novel case, features of POC were identified in association with IC2 hypomethylation on chromosome 11p15, consistent with Beckwith-Wiedemann syndrome. To our knowledge, this represents the first reported case of this association and suggests a potential epigenetic contribution. This scoping review highlights the clinical heterogeneity of POC and the limited understanding of its underlying pathogenesis. The presence of epigenetic alterations in our included case suggests that imprinting disturbances may contribute to a subset of presentations, thus warranting further investigation.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red blood cell enzymatic disorder worldwide. Although many heterozygotes are asymptomatic, affected neonates have an increased risk for hyperbilirubinemia and related complications. In the United States, detection of maternal G6PD heterozygous status often occurs incidentally during expanded carrier screening. We sought to characterize the diagnostic timing, clinical management, and neonatal outcomes among pregnancies complicated by maternal G6PD heterozygous status. We conducted a retrospective cohort study of pregnant individuals with a documented G6PD heterozygous diagnosis who received prenatal care at Baylor College of Medicine-affiliated hospitals between January 2013 and December 2025. Patients were identified through electronic health record queries and confirmed by manual chart review. Maternal demographics, diagnostic pathway, testing modality, medication exposures, and neonatal outcomes were abstracted. Descriptive statistics were used to summarize cohort characteristics. Thirty-six individuals with confirmed G6PD heterozygous status were included. Median maternal age was 31 years (IQR 27.5-38). Most patients identified as Black (66.7%) and non-Hispanic (88.9%), while four (11.1%) identified as Hispanic. Diagnosis occurred prior to the first pregnancy in 11.1% of patients, during pregnancy in 47.2%, and after pregnancy in 41.7%. Molecular testing alone was the most common diagnostic modality (55.6%), followed by enzymatic testing (27.7%) and combined testing (16.7%). Among molecularly characterized G6PD heterozygotes, the most frequent variant was c.202G>A (42.3%), followed by c.563C>T (19.2%). Genetic counseling related to G6PD status was documented for 75.0% of patients. Across 76 pregnancies, 82 neonates were delivered, including 71 singletons, four twin pregnancies, and one triplet pregnancy. Bilirubin measurements were available for 47 neonates, of which elevated bilirubin was documented in 16 (34.0%). Hyperbilirubinemia requiring phototherapy occurred in 12 neonates (25.5%). Infant G6PD enzyme testing was performed in 8 cases, of which 5 showed low enzyme levels. Neonatal hyperbilirubinemia occurred most frequently among pregnancies in which the mother carried the c.202G>A variant in G6PD. Maternal G6PD heterozygous status is often identified incidentally during pregnancy, yet subsequent newborn evaluation remains inconsistent. Although more than one-third of neonates born to heterozygote mothers developed hyperbilirubinemia, infant G6PD testing was infrequently performed. These findings highlight the variability in clinical management for individuals deficient in G6PD and demonstrate that identifying maternal heterozygotes provides an opportunity to improve targeted newborn screening as well as neonatal follow-up procedures.
Nonimmune hydrops fetalis (NIHF) is characterized by abnormal fluid accumulation in ≥ 2 fetal compartments and may be genetic. The incremental diagnostic yield of prenatal exome sequencing (ES) for NIHF following a negative standard workup was previously explored on 22 cases. We report ES findings in the remaining cohort and investigate the incremental yield of genome sequencing (GS) in cases without a definitive diagnosis from exome. Enrollment criteria and exome methodology for the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study were previously reported. Exomes without a definitive diagnosis were reviewed with updated clinical information and had GS if DNA was available. A genetic counselor returned the clinical reports. Overall, 50 exomes yielded 22 (44%) diagnoses and six possible diagnoses (12%). Nine new cases (9/28, 68%) had a diagnosis involving one of the following genes: RIT1, SOS1, RYR1, FLT4, LMOD2, KMT2D, PUF60, and BLTP1. Two additional cases were diagnosed upon reclassification of uncertain variants. GS of eligible ES cases resulted in an incremental diagnostic yield of 7% (1/14). ES and GS in NIHF significantly reduce the number of unexplained cases and guide clinical management and recurrence risks. Currently, the incremental diagnostic yield of GS over ES in NIHF remains under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03911531.
Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder characterized by its main clinical features macrosomia, macroglossia, and abdominal wall defects. BWSp is caused by (epi)genetic chromosome 11p15 alterations with approximately 20%-27% of patients exhibiting mosaic paternal uniparental disomy of chromosome 11p15 (pUPD11p15). In this study, we analyzed 46 newly identified patients with pUPD11p15. We investigated the ratio of mosaicism and the extent of pUPD11(p15) segment length and explored their correlation with the clinical phenotype. Additionally we compared the cardinal and suggestive features of our cohort with previously reported pUPD11p15 patients in the literature. The most common phenotypes in our cohort were lateralized overgrowth, organomegaly and macroglossia. While no correlation was found between the segment length and clinical phenotype, a significant positive correlation was observed between the BWSp clinical score and mosaic ratio in blood. This correlation was primarily driven by macroglossia. In contrast to previously published studies reporting mosaic genome-wide paternal UPD (MGWpUPD) in 2%-19% of patients with pUPD11 and BWSp, this was not detected in our cohort.
Genetic modifiers of Duchenne muscular dystrophy (DMD) that alter disease severity or response to therapy have been reported using natural history or registry data sets of older corticosteroid-treated patients. We tested associations of genetic modifiers on motor function outcomes in young (4 to < 7 years) steroid naïve clinical trial participants. Participants in clinical trials (VBP15-002/003 [n = 48]; VBP15-004 [n = 121]; DNA available for n = 110) were genotyped for eight published genetic modifier loci, and associations of genotypes with baseline motor function defined via an age-adjusted linear model. Corticosteroid drug response was modeled by genotype-stratified placebo vs. steroid treatment at 12- and 24-weeks posttreatment (mixed model for repeated measures). Serum proteome profiles (SomaScan) were stratified by modifier genotype, and modifier-associated biomarkers mapped to muscle cell types using snSeq datasets. Two loci showed association with baseline motor outcomes (LTBP4, DYNLT5). LTBP4 genotype (rs1131620) was associated with baseline (pretreatment) motor function for all five motor tests studied (time to stand from supine velocity, time to run/walk 10 m velocity, time to climb 4 stairs velocity, 6-min walk distance, and NorthStar Ambulatory Assessment). DYNLT5 genotype (rs1060575) was associated with time to stand from supine velocity, time to climb 4 stairs velocity, and time to run/walk 10 m velocity. Stratification of baseline proteome profiles by LTBP4 genotype and mapping of genotype-associated serum proteins to specific cell types in muscle (snRNAseq) suggested that IL-23, IL-6, and IL-17D interacting pathways in muscle capillaries are contributors to disease progression. In contrast, the DYNLT5 genotype was associated with proteosome and chaperonin pathways. Trial Registration: clinicaltrials.gov identifier: NCT02760264, NCT02760277, NCT03439670.
Biallelic pathogenic variants in the CTC1 gene are associated with cerebroretinal microangiopathy with calcifications and cysts (CRMCCs), also known as Coats plus syndrome (CPS; OMIM #612199). This rare multisystem condition is characterized by early childhood onset of intracranial calcifications, leukodystrophy and cysts, along with retinal telangiectasia and exudates (Coats disease). We report a woman referred to genetics with complex multisystem clinical manifestations beginning in her 30s and progressing over two decades. In keeping with classical features of the condition, she presented a complex medical history of pathological bone fractures, gastrointestinal ectasias, and premature aging. In addition, she developed progressive thrombotic microangiopathy-associated kidney disease requiring transplantation, suspected liver cirrhosis, and subcutaneous dystrophic calcifications. Exome sequencing identified compound heterozygous likely pathogenic variants in CTC1, consisting of a previously reported missense variant and a novel truncating variant confirmed in trans. Despite clinical features suggestive of premature aging, telomere length analysis demonstrated low-normal values for age, supporting emerging evidence that telomere shortening is not a consistent feature of CTC1-related disorders. This case represents the second confirmed adult-onset CTC1-related disorder and the longest survival to date. The findings suggest that subcutaneous calcifications and progressive renal and multi-organ disease may represent later-onset manifestations of the condition. TMA may be a pathologic feature of the multi-system impacts of this rare disease in adults.
Short stature is clinically and genetically heterogeneous, and defects in the extracellular matrix of growth plate cartilage represent a key disease mechanism. ACAN encodes aggrecan, the major proteoglycan of the growth plate cartilage extracellular matrix. Heterozygous ACAN variants are a recognized cause of familial short stature, often associated with advanced bone age and early growth cessation, yet they show a broad phenotypic spectrum. We aimed to delineate the clinical and molecular spectrum of ACAN-related short stature in a Turkish cohort. We retrospectively reviewed 47 individuals from 20 unrelated families with short stature (height ≤ -2 SDS) or predicted adult height < -2 SDS. Anthropometric data, dysmorphic and musculoskeletal findings, radiologic assessments, and molecular genetic results were analyzed. Among 47 individuals (20 females, 27 males), 59.6% were children. Common clinical features included a high forehead, upslanted palpebral fissures, a depressed nasal bridge, low-set anteverted ears, mild pectus deformity, and brachydactyly. Osteochondritis dissecans, early-onset osteoarthritis, and advanced bone age were identified in 6.5%, 8.7%, and 28.6% of individuals, respectively. Vertebral findings included scoliosis (19.6%), increased lumbar lordosis (13%), and vertebral endplate changes (10.9%). Genetic testing revealed 15 heterozygous ACAN variants (2 previously reported in ClinVar; 13 novel): 6 nonsense, 2 splice-site, 5 frameshift, and 2 missense. Overall, 45 patients carried pathogenic/likely pathogenic variants (14 variants), and 2 carried VUS (1 variant). ACAN-related short stature represents an important subset of familial short stature. Skeletal and musculoskeletal findings may aid diagnosis, but advanced bone age is not consistent and bone age is often appropriate for chronological age.
Alagille syndrome (ALGS) is a rare, typically multisystem genetic disorder that impacts the liver, heart, eyes, vertebrae, and other areas of development. A clinical diagnosis can be established through defined clinical diagnostic criteria, while a molecular diagnosis requires the presence of a heterozygous pathogenic variant in JAG1 or NOTCH2 detected through molecular genetic testing. Disruption of either gene product results in disrupted Notch signaling pathways, resulting in the broad spectrum of clinical manifestations. The estimated incidence of ALGS is approximately 1 in 30,000-70,000 newborns. Here, we present a case report of a female neonate that presented at birth to the cardiothoracic intensive care unit with critical congenital heart disease (CHD), specifically, Tetralogy of Fallot (ToF). The patient and her parents were enrolled in a translational genomics protocol, COURAGE for Kids, aimed at performing research genome sequencing (GS) on neonates with critical CHD, in a phenotype-agnostic manner, to characterize genetic associations with disease and longitudinal outcomes. This family's GS uncovered a paternally inherited heterozygous missense variant in JAG1 (NM_000214.3:c.806C>T:p.Pro269Leu), which is associated with ALGS type 1 (MIM #118450). Segregation analysis revealed that the proband's paternal grandfather, who also had ToF as a child, carries the same familial variant. A subsequent dysmorphology assessment revealed typical ALGS facial features in the proband, as well as her father, who does not have a history of CHD (prominent forehead, deeply set eyes, wide nasal bridge, bulbous nose, and pointed chin). Thus, this variant is likely causing incomplete ALGS in the proband, father, and paternal grandfather. This variant may have also contributed to vascular events that have occurred within this family, an important example of how an uncovered molecular diagnosis can guide care even for isolated disease. We report a familial JAG1 variant (p.Pro269Leu) in a family with incomplete ALGS presenting as isolated ToF. Given the proband's clinical features alone were not suspicious of a molecular diagnosis of ALGS or other multisystem genetic disorder, this case underscores the potential importance of phenotype-agnostic genetic workup for critical CHD in the neonatal setting.
Peroxisomal fatty acyl-CoA reductase 1 (FAR1) deficiency is a rare single-enzyme peroxisomal disorder caused by biallelic pathogenic variants in FAR1, typically manifesting with severe neurodevelopmental delay, hypotonia, early-onset epilepsy, and congenital cataracts. We report a male infant born to first-cousin parents presenting with severe global developmental delay, refractory seizures, progressive microcephaly, and feeding difficulties, together with a previously unreported finding of imperforate anus. Ophthalmologic examination revealed abnormal macular reflexes without overt cataracts. Brain MRI at 14 months showed diffuse bilateral subcortical and periventricular T2/FLAIR hyperintensities consistent with chronic white matter disease. Metabolic screening was normal. Rhizomelic chondrodysplasia punctata was excluded, and whole-exome sequencing identified a homozygous likely pathogenic canonical splice-site variant (NM_032228.3:c.-7-2A>G) in FAR1. Functional cDNA analysis confirmed skipping of exon 2, supporting a loss-of-function mechanism. Segregation analysis confirmed autosomal recessive inheritance. This single-case observation raises the possibility that the phenotypic spectrum of FAR1 deficiency may extend to gastrointestinal malformations such as imperforate anus, highlights the limitations of routine biochemical testing, and underscores the importance of early whole-exome sequencing for definitive diagnosis and multidisciplinary management.
DeSanto-Shinawi syndrome (DESSH) is a rare autosomal dominant neurodevelopmental disorder associated with heterozygous pathogenic variants in the WAC gene, most commonly resulting in loss of function. The clinical spectrum of DESSH continues to expand, whereas detailed electroencephalographic descriptions remain limited. We report a 9-year-old male patient presenting with developmental delay, behavioral abnormalities, dysmorphic facial features, epilepsy, and congenital cardiac anomalies. Brain magnetic resonance imaging was normal, while serial electroencephalography demonstrated persistent epileptiform activity involving the bilateral temporo-occipital regions, with left temporo-occipital persistence on follow-up. Whole-exome sequencing identified a novel heterozygous apparently de novo frameshift variant in WAC (NM_016628.5:c.1793delT; p.Met598Serfs*8), which was classified as pathogenic according to ACMG/AMP criteria. The variant is predicted to result in loss of function, supporting haploinsufficiency as the most plausible disease mechanism. This case expands the mutational and clinical spectrum of DESSH and provides additional electroclinical data on epilepsy associated with WAC-related neurodevelopmental disorder. The coexistence of ventricular septal defect and bicuspid aortic valve further supports the multisystemic nature of the syndrome. Our findings highlight the importance of detailed neurological, electroencephalographic, cardiac, and genetic evaluation in patients with suspected DESSH.
