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At least 19 recordsLinked to original sources

PubMed2026

Facial Dysmorphism and Severe Vascular Phenotype in TRNT1 Deficiency with Concomitant Antithrombin III Deficiency.

TRNT1 deficiency (SIFD syndrome) is a rare inborn error of immunity characterized by sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay. We report two Romanian patients with genetically confirmed TRNT1 deficiency presenting with characteristic hematologic and immunologic abnormalities and a distinctive facial dysmorphism. One patient additionally developed severe gastrointestinal ischemia and intracranial hemorrhage in the setting of concomitant hereditary antithrombin III deficiency. These observations expand the phenotypic spectrum associated with TRNT1 deficiency and highlight the marked clinical variability of this disorder. The contribution of TRNT1-associated inflammation to the vascular phenotype remains speculative and cannot be distinguished from the effects of the concomitant thrombophilic condition.

Humans↗

PubMed1977

[Ring of the chromosome 4. II. Without facial dysmorphism].

A r(4) was observed in a 5-year-old female patient, with growth retardation, a near normal psychomotor development and with no major dysmorphism. The break points were in p16 and q33. After comparison with other known observations of r(4) it is suggested that the phenotype of monosomy 4p is due to monosomy for the distal band 4p16.

Child, Preschool↗

PubMed2025

The CTDP1 Founder Variant in CCFDN: Insights into Pathogenesis, Phenotypic Spectrum and Therapeutic Approaches.

Congenital Cataracts, Facial Dysmorphism, and Neuropathy (CCFDN) syndrome is a rare autosomal recessive disorder predominantly found among Vlax Roma populations, caused by a deep intronic founder variant in the CTDP1 gene. This review synthesizes recent advances in understanding the molecular mechanisms of CTDP1 dysfunction, highlighting its central role in transcriptional regulation, RNA splicing, DNA repair, and genome integrity. The unique splicing defect caused by the founder disease-causing variant in the Roma population results in a multisystem phenotype with early-onset neuropathy, congenital cataracts, and characteristic facial dysmorphism. Beyond its genetic homogeneity, CCFDN displays variable clinical severity and presents diagnostic challenges due to overlapping syndromic features. We discuss the emerging therapeutic landscape, focusing on antisense oligonucleotides, small molecule modulators, gene replacement, and genome or transcriptome editing strategies, while emphasizing the challenges in targeted delivery and efficacy. Ongoing insights into CTDP1's broader biological functions and population genetics inform new directions for diagnosis, genetic counselling, and the development of effective therapies for this severe yet underrecognized disorder.

Humans↗

PubMed1978

[Intercalary deletions of 9q].

Two interstitial deletions of different segments of 9q are reported. The first deletion (9/11q22) was seen in an 8-year-old boy with severe psychomotor retardation and descrete facial dysmorphism. The second deletion (9q32q34) was seen in a 5-month-old boy with a very peculiar cranio-facial dysmorphism including brachycephaly, frontal bossing, a deep nasal bridge, a short nose, and absence of triradii b, c and d.

Abnormalities, Multiple↗

PubMed2026

First Cornelia de Lange Syndrome Type 4 Caused by the Gonadal Mosaicism of RAD21 Deletion.

BACKGROUND: Cornelia de Lange syndrome (CdLS) currently has seven known causative genes, inherited in an autosomal or X-linked dominant pattern. Clinical features are variable, including dysmorphic facial features, intrauterine and/or postnatal growth retardation, multiple organ system malformations, and neurodevelopmental disorders. Type 4 of CdLS caused by RAD21 gene has a relatively mild phenotype. METHODS: Here, we report a pair of siblings from a Chinese family who both have similar dysmorphic facial features, cleft palate, spina bifida occulta, and limb phenotypes. Whole-genome sequencing (WGS) was performed to analyze the genetic basis of their condition. Gap-PCR was subsequently employed to map the breakpoints in the affected siblings' peripheral blood samples. Additionally, the copy number status of the parents and the father's sperm DNA were evaluated using Gap-PCR and digital PCR (dPCR). RESULTS: Through WGS analysis, a heterozygous deletion was found in the 8q23.3-8q24.11 region of both patients, which includes the full-length RAD21 gene. And we mapped the breakpoint with the peripheral blood samples of the affected siblings using Gap-PCR. The parents' peripheral blood had normal copy number. The father's sperm DNA was negative for the deletion by both Gap-PCR and dPCR, whereas the mother's peripheral blood was also negative, suggesting the deletion is likely due to maternal gonadal mosaicism. CONCLUSIONS: We report a pair of siblings with a complete loss of RAD21, with evidence supporting maternal gonadal mosaicism. This information will be helpful for genetic counseling for Type 4 of CdLS.

Humans↗

PubMed2022

Biallelic variants in ZNF142 lead to a syndromic neurodevelopmental disorder.

Biallelic variants of the gene encoding for the zinc-finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.

Humans↗

PubMed2026

Third Patient With Biallelic Variants in SMAD6 With an Overlapping Phenotype: Developmental Delays, Dysmorphic Features, and Cardiovascular Abnormalities.

SMAD6 encodes an inhibitory SMAD protein that modulates BMP and TGF-β signaling. Heterozygous pathogenic variants in SMAD6 have been primarily associated with aortic valve disease, radioulnar synostosis, and nonsyndromic sagittal and metopic synostosis. However, only two syndromic patients with biallelic variants have been reported in the literature. We report a 4-year-old girl with neurodevelopmental delays, dysmorphic features, complex congenital heart disease, renal asymmetry, and arterial tortuosity. Whole exome sequencing showed two homozygous SMAD6 variants of uncertain significance: c.161G>T (p.Gly54Val) and c.1A>G (p.Met1?). This is the third patient with biallelic SMAD6 variants associated with skeletal changes, more complex cardiovascular phenotype, facial dysmorphism, and novel arterial abnormalities. This suggests biallelic variants may cause a distinct and potentially more severe autosomal recessive syndrome. Functional investigation is needed to determine the molecular consequences of biallelic SMAD6 variants and to inform variant classification and mechanism. This report characterizes a potential unique genetic syndrome associated with biallelic SMAD6 variants, highlighting the importance of additional sequencing, vascular imaging, and multidisciplinary care coordination for these patients.

SMAD6↗

PubMed2026

Association of FOXC1 Duplications With Juvenile Open-Angle Glaucoma.

IMPORTANCE: While FOXC1 single-nucleotide variants and deletions are well-established causes of Axenfeld-Rieger syndrome, few FOXC1 duplications have been reported. This study investigated families with duplications encompassing the FOXC1 gene to refine the associated phenotypic spectrum and contribution to glaucoma. OBJECTIVE: To investigate the prevalence and phenotype of FOXC1 duplications in 2 large glaucoma registries. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational genetic cohort study included participants recruited from the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) and the Massachusetts Eye and Ear (MEE) cohort from 2008 through 2025. Participants with glaucoma, and available relatives, underwent genomic testing to identify duplications encompassing FOXC1 using exome sequencing and genotyping arrays (ANZRAG) or whole-genome sequencing (MEE). Data analyses were conducted from 2022 through 2025. MAIN OUTCOMES AND MEASURES: Prevalence of FOXC1 duplications, age at glaucoma onset, and phenotype, including ocular and systemic features. RESULTS: Twenty individuals from 10 families (50% female and 50% male; 70% self-described as broadly European [Australian/British, British, English/German, English/Polish, European, or Scottish], 25% as Asian [Chinese or Filipino], and 5% as Latin American [Salvadoran]) were identified with FOXC1 duplications. All genetically tested individuals were diagnosed with glaucoma, demonstrating high penetrance. Seventeen individuals were referred with juvenile open-angle glaucoma (JOAG), 1 with primary open-angle glaucoma, 1 with primary congenital glaucoma, and 1 with anterior segment dysgenesis. The diagnosis of 4 individuals from 1 family with ectropion uveae was revised to anterior segment dysgenesis. Systemic features were reported for 2 participants (10.5%), including subtle dental findings and mild facial dysmorphism. Duplications encompassing FOXC1 were among the most common monogenic contributors to JOAG. In the ANZRAG group, they accounted for 13.5% (95% CI, 6.7%-25.3%) of JOAG probands with a genetic diagnosis, second to MYOC (53.8%; 95% CI, 40.5%-66.7%). In the MEE group, FOXC1 duplications accounted for 9.5% (95% CI, 2.7%-28.9%) of JOAG probands with a genetic diagnosis. CONCLUSIONS AND RELEVANCE: These findings suggest FOXC1 duplications are an underrecognized, highly penetrant, but variably expressive, genetic variation associated with JOAG. Findings for the relatively modest number of individuals in the retrospective study were associated with wide confidence intervals. This limitation is often inherent to studies of JOAG, a rare condition for which individual genetic variants account for only a subset of cases. Despite this, the findings highlight the genetic heterogeneity of JOAG and support the potential importance of considering routine genetic copy-number variant analysis for individuals with JOAG.

Humans↗

PubMed2022

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Exons↗

PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗

PubMed2026

35 Individuals With HUWE1-Related Neurodevelopmental Disorder and Suggested Clinical Evaluations.

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well as additional multisystemic findings. Intrauterine growth restriction (IUGR) and feeding difficulties were common in the neonatal period. It is notable that nearly all females had de novo variants, and males had de novo or inherited variants from clinically unaffected carrier mothers. Three genetic hotspots were identified in evolutionarily conserved regions of HUWE1 that have clinical impact. This report provides additional characterization of the spectrum of HUWE1-related neurodevelopmental disorder (HNDD).

Humans↗

PubMed1979

Monosomy 10qter.

An 11-year-old girl with 10q26qter deletion is described and compared with another patient reported in the literature. The most characteristic features of monosomy 10qter seem to be: severe mental retardation; growth retardation; microcephaly; and facial dysmorphism with a long and triangular facies, a broad and prominent nasal bridge, a poorly developed tip of the nose, a short philtrum, and flattened angles of the mandible. Several of these features are opposed in type and countertype to features of trisomy 10qter.

Child↗

PubMed2026

A recurrent CCDC82 frameshift variant associated with syndromic neurodevelopmental disorder in a consanguineous Pakistani family.

BACKGROUND: Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. METHODS: Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. RESULTS: Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. CONCLUSIONS: This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.

Autosomal recessive↗

PubMed2024

Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders.

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

Humans↗

PubMed2026

Expanding the genotypic and phenotypic spectrum of PGAP1 deficiency: clinical and functional insights from 15 patients.

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are essential for neuronal development, synaptic organization and signaling. Defects in GPI-anchor biosynthesis or remodeling cause rare neurodevelopmental disorders, including post-GPI attachment to proteins 1 (PGAP1) deficiency. PGAP1 encodes an inositol deacylase required for GPI-anchor remodeling and appropriate trafficking and membrane localization of GPI-APs. Loss of PGAP1 function disrupts GPI-AP processing, but the clinical spectrum remains incompletely defined because reported cohorts are small. We report 15 individuals with biallelic PGAP1 variants from 11 unrelated families identified through international collaboration. Clinical information was collected using a standardized phenotyping questionnaire and review of available clinical records. The most frequently recorded features were developmental delay or intellectual disability, motor developmental delay, speech impairment, facial dysmorphism, hypotonia and seizures. Independent walking was clearly recorded in a minority of individuals, while feeding, ophthalmological, musculoskeletal and neuroimaging findings were recorded in subsets of the cohort. Clinical investigations were performed as part of routine care and were not uniform across sites. Accordingly, source-dependent assessments including MRI, EEG, EMG/NCS, formal ophthalmology, hearing assessment, systemic imaging, IQ/DQ testing, MRC scoring and anthropometric Z-scores are reported descriptively or using available-data denominators. Spasticity, hypertonia or possible peripheral nerve involvement was recorded in some clinical summaries; however, electrophysiological confirmation was not uniformly available, and confirmed peripheral neuropathy was not analyzed as a cohort-level prevalence outcome. Functional studies in selected patient-derived cells or model systems demonstrated PI-PLC resistance of GPI-APs, supporting impaired GPI-anchor remodeling. These findings expand the genotypic and recorded phenotypic spectrum of PGAP1 deficiency.

Journal Article↗

PubMed2026

Biallelic RDH11 variants cause syndromic retinitis pigmentosa with early-onset cataracts and neurodevelopmental delay: a multicenter case series.

Biallelic variants in the RDH11 gene, a retinol dehydrogenase involved in the visual cycle and systemic retinoid homeostasis, were initially implicated in a rare condition characterized by retinal dystrophy, early-onset cataract, neurodevelopmental anomalies and myopathy, through single-family reports, with this association more recently being confirmed in a larger study. Here, we further establish the pathogenic role of RDH11 by presenting a large multi-center cohort, comprising eight individuals from seven unrelated families. Comprehensive genetic analysis identified homozygous variants in all affected subjects, including two novel variants, strongly supporting loss-of-function as the primary disease mechanism. Detailed clinical phenotyping defined a consistent and severe multisystem disorder. Ophthalmologically, the hallmark features include bilateral congenital or early-childhood cataracts requiring surgical intervention, accompanied by retinitis pigmentosa (RP). In terms of extra-ocular involvement, the cohort exhibited a high prevalence of neurodevelopmental delay, including intellectual disability, autistic spectrum disorder and learning difficulties. These features were frequently accompanied by congenital microcephaly, intrauterine and postnatal growth restriction, facial dysmorphisms, and dental anomalies. By significantly expanding both the mutational and phenotypic spectrum of RDH11-related disease, our findings provide independent replication of this gene-disease association and definitively support RDH11 as a bona fide syndromic RP gene.

Journal Article↗

PubMed2023

Structural and functional insights into a novel homozygous missense pathogenic variant in CUL7 identified in consanguineous Pakistani family.

3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T > C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein's three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.Communicated by Ramaswamy H. Sarma.

Humans↗

PubMed2026

Elucidating the Role of SET as a Key Contributor to Neurodevelopmental Disability Within the 9q34.11 Deletion Syndrome Interval.

The 9q34.11 chromosomal region contains multiple neurodevelopmental genes involved in synaptic transmission, axonal structure and neuronal maturation. Pathogenic microdeletions, duplications and single nucleotide variants in numerous genes were previously linked with neurodevelopmental disorders (NDDs). Amongst them, SET has recently been implicated in a rare NDD with speech delay and facial dysmorphism. This study reports a female with a heterozygous de novo deletion impacting SET but not other NDD-associated genes at 9q34.11. The proband was initially diagnosed with atypical Rett syndrome with overlapping clinical features of SET haploinsufficiency. The deletion was confirmed using microarray and long-read sequencing. Subsequent quantitative proteomic evaluation identified a significant decrease of SET protein in patient-derived fibroblasts compared to control lines. This study provides insights into the proband's clinical course over their 28 year diagnostic odyssey, and emphasises the benefits of early speech therapy interventions. The proband had no functional speech, but regained the capacity to meaningfully communicate and articulate a limited vocabulary in adulthood, concordant with other reported non-paediatric cases of SET-NDD. This study expands current knowledge on the genotypic and phenotypic spectra of SET-NDD, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.

Humans↗