Clinical and genetic analysis of four Chinese pedigrees affected with NAA15-related intellectual developmental disorder

De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review

Despite ample success in reducing coronary artery disease (CAD) risk through reduction of low-density lipoprotein cholesterol (LDL-C), there remains substantial residual risk.1–4 Recent prospective studies have demonstrated that elevated triglycerides (TGs) are independent predictors of CAD risk.5–9 Furthermore, TGs are strongly associated with incident CAD events in patients with low LDL-C levels treated with statin.10 Thus, triglyceride-rich lipoproteins (TRLs) offer a potentially orthogonal risk factor to LDL-C for lowering CAD risk, but only if TRLs are causally associated with atherosclerotic disease.11 Human genetics has the potential to reveal the causal relationships of biomarkers found to be associated with disease outcomes.12–15 For example, genetic variants associated with plasma LDL-C levels are consistently associated with CAD risk in the right direction,15–18 consistent with a causal relationship. Importantly, similar studies have causally implicated the key TG-regulating enzyme lipoprotein lipase (LPL) in CAD risk. A common gain-of-function LPL variant, S447X, confers an antiatherogenic lipid profile characterized by low levels of TGs, and in several studies, it has been associated with lower incidence of vascular disease or myocardial infarction (MI).19–25 Conversely, several loss-of-function (LOF) LPL variants associated with elevated TG levels have been reported to be associated with increased CAD risk.21,26 Furthermore, multiple genome-wide association studies in the last 5 years have identified common noncoding variants at the LPL gene locus associated with both TG and CAD risk in the same direction.27–29 Beyond LPL itself, common variants that influence TG levels are significantly associated with CAD risk even after adjusting for their effects on other lipid traits.30 Do et al30 surveyed 185 single-nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with ≥1 plasma lipid trait and identified a subset of …

Language and communication is very important in social, emotional, and cognitive development of children. Delay in language is the first complaint for children diagnosed with autism spectrum disorder (ASD) or developmental language delay (DLD). In this study it is aimed to evaluate and compare language profiles and autistic symptoms between children diagnosed with ASD, DLD, and healthy controls. Twenty-six children who are diagnosed with ASD, 43 children who are diagnosed with DLD, and 47 healthy controls are included to study; and all children are in the age of 48-72 months. Test of Early Language Development was used to evaluate language profiles, and autism spectrum symptoms were evaluated with social communication questionnaire (SCQ). The sociodemographic features of groups were similar. The statistical significant differences were found in all language subscales and subscales of SCQ among three groups. Both children who were diagnosed with ASD and DLD had more autism spectrum symptoms when compared to controls. In present study, it is indicated that developmental language trajectories are different in ASD and DLD group. Children, who are diagnosed with ASD, have more receptive language difficulties while children, who are diagnosed with DLD, have more language difficulties in expressive language area. The finding, children who are diagnosed with DLD have more autistic symptoms, shows that autistic symptoms are related with language development, and it is very important to give preference to language education in the treatment.

ABSTRACTObjective:To evaluate the concordance between p53 immunohistochemistry (IHC) patterns and TP53 mutation types identified by next-generation sequencing (NGS) in lung adenocarcinoma.Methodology:In this retrospective study, 166 lung adenocarcinoma cases diagnosed between 2020 and 2025 at the Department of Medical Pathology, Karadeniz Technical University Faculty of Medicine were analyzed. p53 IHC staining was classified as overexpression, null, or wild-type. TP53 mutations detected by NGS were categorized as missense, nonsense, frameshift, or splice-site variants. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each IHC pattern for predicting its corresponding mutation class were calculated using NGS as the reference standard.Results:p53 IHC showed overexpression in one hundred eighteen cases (71.1%), a null pattern in forty-two (25.3%), and wild-type staining in six (3.6%). TP53 mutations included missense (74.1%), nonsense (11.4%), frameshift (10.2%), and splice-site variants (4.3%). Overexpression strongly correlated with missense mutations: 117 of 118 overexpression cases (99.2%) carried missense variants. The null pattern was mainly associated with truncating mutations, including nonsense and frameshift variants. Wild-type staining showed heterogeneous profiles. Overexpression predicted missense mutations with a sensitivity of 95.1%, specificity of 97.7%, PPV of 99.2%, and NPV of 87.5%. The null pattern predicted nonsense mutations with moderate PPV but high NPV.Conclusions:p53 IHC is a reliable surrogate marker for identifying TP53 missense mutations in lung adenocarcinoma, with overexpression demonstrating excellent diagnostic accuracy. Although the null pattern has limited PPV for nonsense mutations, its high NPV supports its use in excluding such variants. p53 IHC may serve as a practical and cost-effective approach for inferring TP53 mutation status, particularly in settings where molecular testing is restricted.

BackgroundEpidermolysis Bullosa (EB) is a rare genetic disorder that results in fragile skin and blistering and may lead to mucous membrane involvement. The disease manifests in several subtypes, among which the most serious conditions are dystrophic and junctional EB. This study intends to highlight the recurrent and novel genetic abnormalities that cause EB in the Western region of Saudi Arabia.MethodsTwelve Middle Eastern Arab families affected by Epidermolysis Bullosa (EB) were recruited from dermatology clinic from King Abdullah Medical Complex in Jeddah. Detailed clinical phenotyping was conducted for each patient to document EB-associated symptoms and to accurately determine the disease subtypes. Whole Exome Sequencing (WES) was performed to identify genetic variants associated with EB, and the resulting variants were classified by the guidelines of the American College of Medical Genetics and Genomics (ACMG). Additionally, multiple bioinformatics tools were employed to evaluate the pathogenicity of the detected variants. Variant segregation with disease phenotype was confirmed within the families using Sanger sequencing.ResultsWe identified 11 genetic variants, including three novel variants, in the COL7A1 (NM_000094.4), COL17A1 (NM_000494.4), and LAMB3 (NM_000228.3) genes across 12 EB families. The COL7A1 variants included frameshift variants (c.5924_5927del and c.6268_6269del), nonsense variants (c.1633C > T, c.1837C > T, c.2005C > T, and c.5888G > A), missense variants (c.4448G > A and c.8245G > A), and splice-site variants (c.6751-1G > A and c.8305-1G > A). Additionally, a splice-site variant was identified in COL17A1 (NM_000494.4; c.1394G > A) and another in LAMB3 (NM_000228.3; c.1977-1G > A). Bioinformatics analysis predicted these variants to be likely pathogenic because they disrupt collagen VII, XVII, and laminin 332, proteins essential for skin stability. Frameshift and nonsense variants introduce premature stop codons, leading to truncated or degraded transcripts. Splice-site variants likely cause aberrant splicing, disrupting the reading frame and impairing protein function.ConclusionWES is an effective first-line diagnostic tool for identifying EB-associated variants. This study reveals locus and allelic heterogeneity in EB cases from Saudi Arabia. The findings underscore the importance of early genetic screening for improving genetic counseling in high-consanguinity populations and emphasize the need for large-scale genetic studies in the country.

Epidermolysis Bullosa (EB) is a rare genetic disorder that results in fragile skin and blistering and may lead to mucous membrane involvement. The disease manifests in several subtypes, among which the most serious conditions are dystrophic and junctional EB. This study intends to highlight the recurrent and novel genetic abnormalities that cause EB in the Western region of Saudi Arabia. Twelve Middle Eastern Arab families affected by Epidermolysis Bullosa (EB) were recruited from dermatology clinic from King Abdullah Medical Complex in Jeddah. Detailed clinical phenotyping was conducted for each patient to document EB-associated symptoms and to accurately determine the disease subtypes. Whole Exome Sequencing (WES) was performed to identify genetic variants associated with EB, and the resulting variants were classified by the guidelines of the American College of Medical Genetics and Genomics (ACMG). Additionally, multiple bioinformatics tools were employed to evaluate the pathogenicity of the detected variants. Variant segregation with disease phenotype was confirmed within the families using Sanger sequencing. We identified 11 genetic variants, including three novel variants, in the COL7A1 (NM_000094.4), COL17A1 (NM_000494.4), and LAMB3 (NM_000228.3) genes across 12 EB families. The COL7A1 variants included frameshift variants (c.5924_5927del and c.6268_6269del), nonsense variants (c.1633C > T, c.1837C > T, c.2005C > T, and c.5888G > A), missense variants (c.4448G > A and c.8245G > A), and splice-site variants (c.6751-1G > A and c.8305-1G > A). Additionally, a splice-site variant was identified in COL17A1 (NM_000494.4; c.1394G > A) and another in LAMB3 (NM_000228.3; c.1977-1G > A). Bioinformatics analysis predicted these variants to be likely pathogenic because they disrupt collagen VII, XVII, and laminin 332, proteins essential for skin stability. Frameshift and nonsense variants introduce premature stop codons, leading to truncated or degraded transcripts. Splice-site variants likely cause aberrant splicing, disrupting the reading frame and impairing protein function. WES is an effective first-line diagnostic tool for identifying EB-associated variants. This study reveals locus and allelic heterogeneity in EB cases from Saudi Arabia. The findings underscore the importance of early genetic screening for improving genetic counseling in high-consanguinity populations and emphasize the need for large-scale genetic studies in the country.

Mutations in twenty genes have been associated with heritable breast cancer (BCA), yet the prevalence and clinical implications of most of these genes have not been well described in African American women (AAW). AAW who harbor inherited mutations in BCA susceptibility (BCS) genes are less likely to be identified and thus less likely to receive standard of surgical and preventive care for heritable BCA. A better understanding of heritable mutations in AAW with BCA would ultimately help to define guidelines for clinical management of high risk AAW. We performed targeted sequencing for 288 AAW diagnosed with invasive BCA unselected for family history, age, or BCA subtype. Participants were enrolled in the Detroit Research on Cancer Survivors (ROCS) cohort study or the Karmanos Cancer Institute Biobank. A custom sequencing panel captured the coding sequence of 43 genes (Known: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53; Candidate: MLH1, MSH2, PMS1, SEC23B, BLM, ATR, BAP1, BBC3, CDKN1A, FAM175A, FANCA, FANCC, FANCI, FANCL, FANCM, GEN1, RAD51B, RBBP8, RECQL, RINT1, TP53BP1, XRCC1, XRCC3). Samples were sequenced using the Illumina MiSeq platform multiplexed for 100X mean depth of coverage. Intronic or synonymous exonic variants and those with <40 reads, or alternative allele frequency >3% in African populations in the 1000 Genomes, ExAC, or NHLBI ESP6500SI databases were filtered. Only variants in known BCS genes could be considered definitively pathogenic (DP), defined as missense variants categorized as pathogenic in ClinVar and all frameshift, nonsense, and splice site variants. All other variants were defined as variants of uncertain significance (VUS). We identified 54 women harboring DP mutations in 15 known BCS genes. Mutations in BRCA1/2 accounted for 32% of all DP mutations. Notably, nearly 17% of DP mutations were in MSH6, a gene only recently described as associated with increased risk of BCA in the general population. Among women with these DP mutations, nearly 25% had no high-risk characteristics. Ten VUS in known BCS genes were identified, where 4 were reported in ClinVar (BARD1, RAD5C, BRCA2, PMS2) and 6 were novel (PMS2, BRCA1, MUTYH, MSH6, NBN, MRE11). Among the candidate BCS genes, 63 VUS were identified: 51 frameshift variants, 5 nonsense variants, 3 splice site variants, and 4 missense mutations predicted to be pathogenic by ≥8/9 algorithms. Nearly 60% of participants had neither a DP mutation or VUS. These data suggest that AAW with BCA have a unique mutation spectrum and may benefit from BCS gene sequencing regardless of family history, age, or subtype. Additional sequencing in AAW will lay the foundation for identification of germline factors associated with BCA risk and prognosis specifically in AAW and offer opportunities for personalized risk assessment. Citation Format: Kristen Purrington, Gregory Dyson, Douglas Craig, Julie Boerner, Julie Madden, Jennifer Beebe-Dimmer, Ann G. Schwartz, Michael Simon. Spectrum of heritable mutations in 43 known and candidate breast cancer susceptibility genes in African American women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4175.

Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent eyebrows, a wide mouth, delayed bone age, and hypoplastic or absent fifth fingers/toes or nails, together with developmental delay. The cause of CSS is suggested to be related to alterations in the BRG- or HRBM-associated factor (BAF) pathway in humans. In this gene family, pathogenic variations in the AT-rich interactive domain-containing protein 1B (ARID1B) gene are revealed to be a significant element causing neurodevelopmental disability in patients with CSS. Herein, we describe the clinical features and gene variations in four Chinese patients with CSS. All the patients shared common features of short fifth fingers/toes or hypoplastic nails, coarse facial features, thick eyebrows, long cilia, a flat nasal bridge, a broad nose, a wide mouth, a high palate, and hypotonia. Besides, they had an intellectual disability, language, and motor developmental delay. Candidate genes were screened for variations using polymerase chain reaction (PCR) and sequencing. The variations were sequenced by next-generation sequencing and confirmed by first-generation sequencing. Exome sequencing suggested four de novo variations in the ARID1B gene in four unrelated patients. These included two frameshift variations (c.3581delC, c.6661_6662insG) and two nonsense variations (c.1936C>T, c.2248C>T). Of the four variations, three variations were novel. The results in our present study broaden the understanding of the disease and further interpret the molecular genetic mechanism of these rare variations in CSS.

A clinical analysis of children with developmental delay.

Deep resequencing and association analysis of schizophrenia candidate genes.

Clinical and molecular analysis of Guangxi patients with Kabuki syndrome and KMT2D mutations

Intellectual disability (ID) is a neurodevelopmental disorder, characterized by congenital cognitive and adaptive behavioral issues. We studied multiple patients with ID born to consanguineous parents. Exome sequencing was completed for selected patients and the data were filtered using an allele frequency of less than 0.01. All exonic and splice-site variants were considered. Segregation analyses were performed using allele-specific PCR and Sanger sequencing. Expression analyses of candidate genes were determined after cDNA synthesis from the mouse brain. Clinical evaluations revealed that the patients in the four families exhibited different degrees of cognitive impairments. Patients in two families had no other phenotypes while those from the other two families also manifested disorders such as epilepsy. In family PKID01, a known homozygous missense variant of UFSP2 was found to segregate with the phenotype. We also identified four biallelic novel variants including missense, frameshift, and nonsense variants in ATP13A2, QPCTL, WDR62 and FMO4 in the affected patients from three families. Among these, the QPCTL variant pinpoints a new candidate gene for ID. This study expands the genetic etiology of ID. Intrafamilial genetic heterogeneity underscored the difficulties of molecular characterization of ID in even small nuclear consanguineous families. This research yielded only the second family in literature with a homozygous FMO4 variant, strengthening its candidature with ID.

SATB2-associated syndrome (SAS) is a multisystemic disorder characterized by developmental delay, moderate to profound intellectual disability, speech delay and/or absent speech, behavioral issues such as autistic tendencies, agitation or aggressive outbursts, self-injury, impulsivity, hyperactivity, anxiety and sleeping difficulties. Alterations in the SATB2 gene have been identified as pathogenic causes of SAS. No formal clinical diagnostic criteria have been established for SAS, and molecular disruption of SATB2 is necessary to confirm the diagnosis. To investigate the molecular pathogenesis of five sporadic patients with intellectual disability, and to delineate the comprehensive clinical characteristics of SAS patients. Whole-exome sequencing analysis was performed in five unrelated patients, and RNA analysis was employed to validate the impact of genetic variation on aberrant splicing. Five SATB2 variants were identified, three of which were novel, including three frameshift variants, one nonsense variant, and a missense variant resulting in aberrant splicing was verified by RNA analysis. A comparative analysis was conducted between the clinical features of our patients and those reported in the literature. In addition to intellectual disability and impaired speech, abnormalities in palmar creases and postnatal growth delay were highlighted as clinically significant features for the diagnosis of SAS. Language regression, as well as joints and fingers abnormalities were also observed in our cohort. Our findings demonstrate that effective mRNA analysis is helpful for understanding the pathogenic mechanisms of novel variants. This study broadens the genetic and phenotypic spectrum of SAS and enhances our knowledge to facilitate accurate genetic counseling and appropriate treatment options.

X-linked intellectual disability, also known as X-linked mental retardation, is a neurodevelopmental disorder caused by a gene defect on the X chromosome. While more than 100 genes have been linked to X linked intellectual disability, the genetic aetiology of intellectual disability remains unknown in approximately half of the cases. Intellectual disability often co-occurs with other conditions like epilepsy and autism spectrum disorder. X-linked 98-related intellectual disability syndrome is a rare neurodevelopmental disorder due to Neurite extension and migration factor gene mutation characterised by global developmental delay, intellectual disability, and language delay, with or without autistic features. Distinctive characteristics include coarse facial features, a protruding tongue, and behavioural abnormalities such as excessive tantrums and intrusiveness. The case study presented involves a child with a stop-gain variant in the Neurite extension and migration factor gene presenting with autism spectrum disorder, specific learning disability and behavioural abnormalities with interesting phenotypic features.

Objective: To discuss the clinical and genetic features of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures (IDDBCS). Methods: The clinical and genetic records of a patient who was diagnosed with IDDBCS caused by PHF21A gene variation at Children's Hospital Capital Institute of Pediatrics in 2021 were collected retrospectively. Using " PHF21A gene" as the keyword, relevant articles were searched at CNKI, Wanfang Data and PubMed from establishment of databases to February 2023. Clinical and genetic features of IDDBCS were summarized in the combination of this case. Results: An 8 months of age boy showed overgrowth (height, weight and head circumference were all higher than the 97th percentile of children of the same age and sex) and language and motor developmental delay after birth, and gradually showed autism-like symptoms like stereotyped behavior and poor eye contact. At 8 months of age, he began to show epileptic seizures, which were in the form of a series of spastic seizures with no reaction to adrenocorticotropic hormone but a good response to vigabatrin. Physical examination showed special craniofacial appearances including a prominent high forehead, sparse eyebrows, broad nasal bridge, and downturned mouth with a tent-shaped upper lip. The patient also manifested hypotonia. Whole exome sequencing showed a de novo heterogeneous variant, PHF21A (NM_001101802.1): c.54+1G>A, and IDDBCS was diagnosed. A total of 6 articles (all English articles) were collected, involving this case and other 14 patients of IDDBCS caused by PHF21A gene variation. Clinical manifestations were intellectual disability or developmental delay (15 patients), craniofacial anomalies (15 patients), behavioral abnormalities (12 patients), seizures (9 patients), and overgrowth (8 patients). The main pathogenic variations were frameshift variations (8 patients). Conclusions: IDDBCS should be considered when patients show nervous developmental abnormalities, craniofacial anomalies, seizures and overgrowth. PHF21A gene variation detection helps to make a definite diagnosis.