PACS1 Syndrome is an ultra-rare neurodevelopmental disorder characterized by intellectual disability, behavioral disturbances, and multisystem involvement. While clinical knowledge is growing, its impact on quality of life (QoL) has not been systematically evaluated, and it is critical to understand the lived experience and psychosocial well-being of these individuals beyond strictly medical outcomes. This study aimed to assess QoL in individuals aged 4-21 years with PACS1 Syndrome using the validated KidsLife scale, proxy-reported by primary caregivers, given the intellectual disabilities and communicative limitations of this population. Twenty-one participants from Spain and other countries were recruited through the Spanish PACS1 Association, and 39 questionnaires from mothers and fathers were analyzed. The KidsLife scale provides standardized scores across eight QoL domains and a global QoL index (QoLI). The mean QoLI was 48.1 ± 28.3, slightly below the median for individuals with intellectual disability, but higher than other neurodevelopmental disorders such as Cornelia de Lange Syndrome. The findings revealed a pattern: while domains related to social inclusion, rights, and physical and material well-being were relatively preserved, reflecting adequate care and access to resources, the most significant compromises were observed in autonomy-related domains, specifically self-determination, interpersonal relationships, and personal development. Most individuals showed a high degree of dependency, and those with greater dependency exhibited lower QoL scores. This situation led more than half of families to reduce their working hours, with caregiving responsibilities disproportionately falling on mothers. Although no statistically significant differences were found between parental ratings, mothers tended to report higher QoL. These findings reflect the substantial functional impact of PACS1 Syndrome and emphasize the need for multidisciplinary support to improve autonomy, social participation, and overall well-being.

The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While NIPBL variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of MAU2 in disease is unclear. We describe 18 individuals carrying 15 heterozygous MAU2 variants and demonstrate pathogenicity through functional analyses. In-frame MAU2 variants predominantly impair NIPBL-MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. Most individuals exhibit a DNA methylation profile compatible with the CdLS episignature. We also describe two MAU2-specific episignatures that reflect variant-dependent molecular consequences. Affected individuals display a wide range of phenotypes, from classic CdLS to milder presentations, with short stature and microcephaly as major features. A heterozygous Mau2 knockout mouse model recapitulates these traits, confirming the causal role of MAU2 disruption in vivo. Our study establishes MAU2 as a CdLS-associated gene and delineates a MAU2-related chromatinopathy with variable expressivity.

Despite significant advances in gene discovery, the molecular basis of many rare genetic disorders remains poorly understood. The concept of disease modules, clusters of functionally related genes whose disruption leads to overlapping phenotypes, offers a valuable framework for interpreting these conditions. However, identifying such relationships remains particularly challenging in ultra-rare syndromes due to the limited number of documented cases. We hypothesized that AI-based facial phenotyping could aid in identifying shared molecular mechanisms by detecting phenotypic convergence among clinically related syndromes. To test this, we used Schuurs-Hoeijmakers syndrome (SHMS; OMIM #615009), caused by a recurrent de novo variant in PACS1, as a model to explore potential phenotypic and functional associations with PACS2-related disorder (DEE66; OMIM #618067) and WDR37-related disorder (NOCGUS; OMIM #618652). Facial photographs of individuals with SHMS were analyzed using the DeepGestalt and GestaltMatcher algorithms. In addition to consistently recognizing SHMS as a distinct clinical entity, the algorithms frequently matched DEE66 and NOCGUS, suggesting a shared facial gestalt. Binary comparisons further confirmed overlapping craniofacial features among the three disorders. These findings were supported by literature review, indicating clinical overlapping and potential functional associations. Overall, our results confirm the presence of consistent facial similarities among PACS1-, PACS2-, and WDR37-related syndromes and highlight the utility of AI-driven facial phenotyping as a complementary tool for uncovering clinically relevant relationships in ultra-rare genetic disorders.

The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While NIPBL variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of MAU2 in disease is unclear. We describe 18 individuals carrying 15 heterozygous MAU2 variants and demonstrate pathogenicity through functional analyses. MAU2 in-frame variants predominantly impair NIPBL-MAU2 interaction, whereas truncating variants cause MAU2 haploinsufficiency and lead to NIPBL reduction. Most patients exhibit a DNA methylation profile compatible with the CdLS episignature. We also identified two MAU2-specific episignatures that reflect variant-dependent molecular consequences. Affected individuals display a wide range of phenotypes, from classic CdLS to milder presentations, with short stature and microcephaly as consistent features. A heterozygous Mau2 knockout mouse model recapitulated these traits, confirming the causal role of MAU2 disruption in vivo. Our study establishes MAU2 as a new CdLS-associated gene and delineates a MAU2-related chromatinopathy with variable expressivity.

Postzygotic mosaicism (PZM) has been increasingly recognized in Cornelia de Lange syndrome (CdLS). However, it has been scarcely described when the genetic cause resides in SMC1A, an X-linked cohesin member implicated in approximately 5% of cases. Here, we report the first female patient with classic CdLS harboring a PZM variant in SMC1A and provide a comprehensive characterization of mosaicism in this gene. The identified PZM variant [SMC1A:NM_006306.3:c.2369 = /G > A; p.(Arg790Gln)], was detected in blood and buccal swab-derived DNA at around 30% allele frequency. Molecular dynamics simulations suggest that this mutation disrupts the elbow domain of SMC1A, potentially impairing cohesin function. Further delineation of phenotypes and genotypes associated with PZM variants in SMC1A reveals that, similar to constitutive variants, mosaic mutations are predominantly missense and distributed throughout the gene. Moreover, the phenotype of patients carrying mosaic variants is clinically indistinguishable from those with constitutive mutations, and purifying selection of the pathogenic variant in blood is suggested, as previously observed in NIPBL-related CdLS. However, this process may be more complex in SMC1A due to its X-linked nature. Our findings underscore the importance of high-sensitivity sequencing techniques for detecting mosaicism and highlight the complexity of X-linked mosaic variants in disease expressivity. Further functional studies and larger cohorts are crucial to improve genotype-phenotype correlations and diagnostics in CdLS.

Bainbridge-Ropers Syndrome (BRPS) is a genetic condition resulting from truncating variants in the ASXL3 gene. The clinical features include neurodevelopmental and language impairments, behavioral issues, hypotonia, feeding difficulties, and distinctive facial features. In this retrospective study, we analyzed 22 Spanish individuals with BRPS, aiming to perform a detailed clinical and molecular description and establish a genotype-phenotype correlation. We identified 19 ASXL3 variants, nine of which are novel. We documented recurrence in nontwin siblings due to parental mosaicism. The predominant prenatal finding was intrauterine growth restriction (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia (85.7%), and gastroesophageal reflux disease (82.4%). Later in life, intellectual disability, language impairment, autism spectrum disorder (75%), and joint laxity (73.7%) were noted. Individuals with variants in the 3' mutational cluster region (MCR) of exon 12 exhibited more perinatal feeding problems, and those with variants in the 5' MCR of exon 11 displayed lower percentiles in height and occipitofrontal circumference, as well as higher frequency of arched eyebrows. This study is the first characterization of a Spanish BRPS cohort, with more than 50 clinical features analyzed, representing the most detailed phenotypic analysis to date.

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis.Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved.Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early.

Cornelia de Lange syndrome (CdLS, OMIM #122470, #300590, #300882, #610759, and #614701) is a rare congenital disorder that affects the development of multiple organs and is characterized by physical abnormalities and cognitive and behavioral disabilities. Its molecular basis is mainly based on alterations in genes encoding structural and regulatory proteins related to the cohesin complex. Moreover, other transcriptional regulatory factors have been linked to this syndrome. However, additional causative genes are still unknown, since many patients still lack a molecular diagnosis. Herein, we describe a case with multiple affected family members presenting with an intragenic duplication in the AFF2 gene. The direct tandem intragenic duplication of exons 10, 11 and 12 was detected through high-resolution array Comparative Genomic Hybridization and next-generation sequencing technologies. Confirming the X-linked inheritance pattern, the duplication was found in the patient, his mother and his maternal aunt affected (dizygotic twins). Targeted sequencing with Oxford Nanopore Technologies revealed an aberrant transcript which is predominantly expressed in the patient and his aunt. Along with these results, a significant reduction in AFF2 gene expression levels was detected in these two individuals. Clinically both subjects exhibit a classic CdLS phenotype, whereas the mother is mostly unaffected. Consistent with the phenotypical differences observed between the mother and the aunt, there is a marked difference in X-inactivation patterns skewing. Given the crucial role of AFF2 in transcriptional regulation, it is not surprising that AFF2 variants can give rise to CdLS phenotypes. Therefore, the AFF2 gene should be considered for the molecular diagnosis of this syndrome.

The aim of this study was to expand knowledge about endocrine disorders in individuals with Cornelia de Lange syndrome (CdLS), a rare developmental genetic disorder with anomalies in multiple organs and systems. Hormone levels, clinical scores, anthropometric measurements, and molecular analysis were assessed in 24 individuals with CdLS. Hyperprolactinemia was the most common endocrine disorder. Three patients showed subclinical hypothyroidism. Concerning the gonadotropic axis, mildly delayed puberty was observed, as well as genital anomalies, such as cryptorchidism. Despite short stature, levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 tended to be normal. Three prepubertal individuals without risk factors had higher than normal values for the homeostatic model assessment of insulin resistance (HOMA-IR) and for insulinemia, suggesting insulin resistance. Furthermore, two adults had elevated body mass indexes associated with HOMA-IR values over the cut-off values. CdLS may lead to dysregulation of the endocrine system, particularly in patients with high HOMA-IR values and insulinemia who are at risk of insulin resistance. Therefore, clinical follow-up with comprehensive hormonal assessment appears warranted in individuals with CdLS.

El síndrome de Cornelia de Lange (SCdL) es una enfermedad rara congénita del desarrollo con afectación multisistémica. Las manifestaciones clínicas son muy variables, pero se distingue entre un fenotipo clásico, caracterizado por unos rasgos craneofaciales distintivos, retraso del crecimiento pre y posnatal, defectos por reducción de las extremidades, hirsutismo y discapacidad intelectual, y un fenotipo no clásico, generalmente más leve y más difícil de diagnosticar. Además, las características clínicas se superponen con las de otros trastornos del neurodesarrollo, por lo que la utilización de criterios clínicos consensuados y de herramientas de inteligencia artificial puede ser útil para confirmar el diagnóstico.En más del 60% de los pacientes se han identificado variantes patogénicas en el gen NIPBL, que codifica una proteína relacionada con el complejo de la cohesina, y en otro 15% en 4 genes también asociados a este complejo: SMC1A, SMC3, RAD21 y HDAC8. Los progresos en las técnicas de secuenciación masiva han permitido describir otros genes relacionados (BRD4, ANKRD11 y MAU2), pero la ausencia de diagnóstico molecular en el 15% de los casos y la gran heterogeneidad clínica del síndrome sugieren la existencia de otros genes y mecanismos relacionados.Aunque no haya un tratamiento curativo, sí hay tratamientos sintomáticos/paliativos que deben ser conocidos por el pediatra. La principal complicación médica en el SCdL clásico es el reflujo gastroesofágico, que debe ser tratado de forma precoz y contundente, ya que es una de las causas más frecuentes de fallecimiento en estos pacientes.

Background: Cornelia de Lange syndrome (CdLS) is a rare polymalformative genetic disorder with multisystemic involvement. Despite numerous clinical and molecular studies, the specific evaluation of the quality of life (QoL) and its relationship with syndrome-specific risk factors has not been explored. Methods: The QoL of 33 individuals diagnosed with CdLS, aged between 4 and 21 years, was assessed using the Kidslife questionnaire. Specifically, the influence of 14 risk factors on overall QoL and 8 of its domains was analyzed. Results: The study revealed below-median QoL (45.3 percentile), with the most affected domains being physical well-being, personal development, and self-determination. When classifying patients based on their QoL and affected domains, variants in the NIPBL gene, clinical scores ≥11, and severe behavioral and communication issues were found to be the main risk factors. Conclusions: We emphasize the need for a comprehensive approach to CdLS that encompasses clinical, molecular, psychosocial, and emotional aspects. The "Kidslife questionnaire" proved to be a useful tool for evaluating QoL, risk factors, and the effectiveness of implemented strategies. In this study, we underscore the importance of implementing corrective measures to improve the clinical score. Furthermore, we highlight the necessity of applying specific therapies for behavioral problems after ruling out underlying causes such as pain or gastroesophageal reflux and implementing measures that facilitate communication and promote social interaction.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Background: PACS1 neurodevelopmental disorder (PACS1-NDD) (MIM# 615009) is a rare autosomal dominant disease characterized by neurodevelopmental delay, dysmorphic facial features, and congenital malformations. Heart disease (HD) is frequently present in individuals with PACS1-NDD, but a compressive review of these anomalies and an evaluation of cardiac function in a cohort of patients are lacking. Methods: (i) Cardiac evaluation in 11 PACS1-NDD patients was conducted using conventional echocardiography. (ii) Heart function was assessed by tissue Doppler imaging, and two-dimensional speckle tracking was performed in seven patients and matched controls. (iii) This systematic review focused on determining HD prevalence in individuals with PACS1-NDD. Results: In our cohort, 7 of 11 patients presented HD. (Among them, three cases of ascending aortic dilatation (AAD) were detected and one mitral valve prolapse (MVP).) None of the patients showed echocardiographic pathological values, and the left global longitudinal strain was not significantly different between patients and controls (patients −24.26 ± 5.89% vs. controls −20.19 ± 1.75%, p = 0.3176). In the literature review, almost 42% (42/100) of individuals with PACS1-NDD reportedly experienced HD. Septal defects were the most common malformation, followed by patent ductus arteriosus. Conclusions: Our results show a high prevalence of HD in PACS1-NDD patients; in this way, AAD and MVP are reported for the first time in this syndrome. Furthermore, a detailed cardiac function evaluation in our cohort did not reveal evidence of cardiac dysfunction in individuals with PACS1-NDD. Cardiology evaluation should be included for all individuals with Schuurs-Hoeijmakers syndrome.

Snijders Blok–Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51–74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.

This study assesses a possible cardiac dysfunction in individuals with Cornelia de Lange syndrome (CdLS) without diagnosed congenital heart disease (CHD) and its association with other factors. Twenty patients and 20 controls were included in the study divided into three age-dependent groups (A: < 10 yrs, B: 10-20 yrs, C: > 20 yrs), and were evaluated using conventional echocardiography, tissue doppler imaging (TDI), two-dimensional speckle tracking and genetic and biochemical analyses. The left ventricular global longitudinal strain (GLS) was altered (< 15.9%) in 55% of patients, being pathological in the older group (A: 19.7 ± 6.6; B: -17.2 ± 4.7; C: -13.6 ± 2.9). The speckle tracking technique revealed a downward trend in the values of strain, strain rate and velocity, especially in the oldest group. Likewise, the ejection fraction (LVEF) and shortening fraction (LVFS) values, although preserved, also showed a decreased with age (p < 0.05). The analytical markers of cardiovascular risk and cardiac function showed no alterations. The molecular analyses revealed 16 individuals carrying pathogenic variants in NIPBL, two with variants in SMC1A, one with a variant in RAD21 and one with a HDAC8 variant. This is the first systematic approach that demonstrates that individuals with CdLS may present early cardiomyopathy, which can be detected by speckle tracking technique even before the appearance of clinical symptoms and the alteration of other echocardiographic or analytical parameters. For all these reasons, cardiological followup is suggested even in the absence of CHD, especially from adolescence onwards.

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.