UNASSIGNED: Smith-Lemli-Opitz syndrome (SLOS), a genetic developmental disorder characterized by various congenital anomalies, arises from a loss of normal DHCR7 enzymatic action in cholesterol biosynthesis. This syndrome is typically marked by various congenital anomalies, including microcephaly with cognitive impairments, distinctive facial features, and syndactyly of the toes (2-3 fusion).
UNASSIGNED: A 73-year-old woman, followed up on by the neurology clinic for the last 3 years for amnesia and movement disorders, was referred to our clinic for genetic etiology investigation. Although there were no significant dysmorphic findings on her physical examination, observations included partial syndactyly between the second and third toes of both feet, a wide forehead, and a triangular face. We used the whole-exome sequencing (WES) analysis to evaluate the patient because of their various phenotype, which included dysmorphic features, movement problems, recurrent hip dislocation, mild intellectual impairment. WES analysis revealed a homozygous missense c.1295A>G (p.Tyr432Cys) variation in DHCR7 gene.
UNASSIGNED: A total of 9 patients with p.Tyr432Cys variant have been reported in the literature so far. The present case is the first patient with biallelic c.1295A>G (p.Tyr432Cys) variation in DHCR7 gene in the current literature. Diagnosing the disorder can be challenging, particularly in its milder manifestations, given the extensive range of clinical presentations. The present case is the oldest patient with SLOS reported in the relevant literature. Mild dysmorphic features, mild intellectual disability, and recurrent hip dislocation, along with the typical finding of syndactyly between the second and third toes in the foot, may indicate mild forms of SLOS.

BACKGROUND: Early Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions.
METHODS: A data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders.
RESULTS: In both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use.
CONCLUSIONS: This data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.

22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease that affects individuals of diverse racial and ethnic backgrounds. There is currently no cure for ALS, and the number of efficient disease-modifying drugs for ALS is limited to a few, despite the large number of clinical trials conducted in recent years. The latter could be attributed to the significant heterogeneity of ALS clinical phenotypes even in their familial forms. To address this issue, we conducted postmortem genetic screening of two female patients with sporadic ALS (sALS) and contrasting clinical phenotypes. The results demonstrated that despite their contrasting clinical phenotypes, both patients had rare pathologic/deleterious mutations in five genes: ACSM5, BBS12, HLA-DQB1, MUC20, and OBSCN, with mutations in three of those genes being identical: BBS12, HLA-DQB1, and MUC20. Additional groups of mutated genes linked to ALS, other neurologic disorders, and ALS-related pathologies were also identified. These data are consistent with a hypothesis that an individual could be primed for ALS via mutations in a specific set of genes not directly linked to ALS. The disease could be initiated by a concerted action of several mutated genes linked to ALS and the disease\'s clinical phenotype will evolve further through accessory gene mutations associated with other neurological disorders and ALS-related pathologies.

BACKGROUND: Despite the introduction of dimensional conceptualisations of personality functioning in the latest classification systems, such as Criterion A of the Alternative Model of Personality Disorders in the DSM-5, heterogeneous clinical presentation of personality pathology remains a challenge. Relatedly, the latent structure of personality pathology as assessed by the Semi-Structured Interview for Personality Functioning DSM-5 (STiP-5.1) has not yet been comprehensively examined in adolescents. Therefore, this study aimed to examine the latent structure of the STiP-5.1, and, based on those findings, to describe any unique clinical profiles that might emerge.
METHODS: The final sample comprised 502 participants aged 11-18 years consecutively recruited from a specialised personality disorder outpatient service, as well as general day clinic and inpatient wards at the University Hospital University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University Hospital Bern, Switzerland. Participants were assessed using the STiP-5.1, as well as a battery of other psychological measures by clinical psychologists or trained doctoral students. Variations of Factor Analysis, Latent Class Analysis and Factor Mixture Models (FMM) were applied to the STiP-5.1 to determine the most appropriate structure.
RESULTS: The best fitting model was an FMM comprising four-classes and two factors (corresponding to self- and interpersonal-functioning). The classes differed in both overall severity of personality functioning impairment, and in their scores and clinical relevance on each element of the STiP-5.1. When compared to the overall sample, classes differed in their unique clinical presentation: class 1 had low impairment, class 2 had impairments primarily in self-functioning with high depressivity, class 3 had mixed levels of impairment with emerging problems in identity and empathy, and class 4 had severe overall personality functioning impairment.
CONCLUSIONS: A complex model incorporating both dimensional and categorical components most adequately describes the latent structure of the STiP-5.1 in our adolescent sample. We conclude that Criterion A provides clinically useful information beyond severity (as a dimensional continuum) alone, and that the hybrid model found for personality functioning in our sample warrants further attention. Findings can help to parse out clinical heterogeneity in personality pathology in adolescents, and help to inform early identification and intervention efforts.

The SYN1 gene encodes synapsin I, variants within the SYN1 gene are linked to X-linked neurodevelopmental disorders with high clinical heterogeneity, with reflex epilepsies (REs) being a representative clinical manifestation. This report analyzes a Chinese pedigree affected by seizures associated with SYN1 variants and explores the genotype-phenotype correlation. The proband, a 9-year-old boy, experienced seizures triggered by bathing at the age of 3, followed by recurrent absence seizures, behavioral issues, and learning difficulties. His elder brother exhibited a distinct clinical phenotype, experiencing sudden seizures during sleep at the age of 16, accompanied by hippocampal sclerosis. Whole exome sequencing (WES) confirmed a pathogenic SYN1 variant, c.1647_1650dup (p. Ser551Argfs*134), inherited in an X-linked manner from their mother. Notably, this variant displayed diverse clinical phenotypes in the two brothers and one previously reported case in the literature. Retrospective examination of SYN1 variants revealed an association between truncating variants and the pathogenicity of REs, and non-truncating variants are more related to developmental delay/intellectual disability (DD/ID). In summary, this study contributes to understanding complex neurodevelopmental disorders associated with SYN1, highlighting the clinical heterogeneity of gene variants and emphasizing the necessity for comprehensive genetic analysis in elucidating the pathogenic mechanisms of such diseases.

BACKGROUND: Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism caused due to mutations in the copper transporter ATP7B. There is often a striking variability of clinical manifestations among patients with ATP7B mutations, including in siblings. This phenomenon may be caused by individual differences in copper accumulation in hepatocytes and intolerance to copper toxicity as governed by genetic variations in copper metabolism genes acting as modifier loci to the disease.
OBJECTIVE: To elucidate the genetic basis of striking clinical heterogeneity among two siblings of two families with WD.
METHODS: The disease diagnosis and subsequent clinical examinations were performed by expert clinicians. The younger siblings in both families presented with early neurological manifestations at a younger age than their older siblings. Interestingly, only the younger siblings were reported to have had hepatic manifestations. Exome sequencing of all the four individuals was performed to understand their heterogeneous phenotypic outcomes.
RESULTS: Genetic screening revealed no difference in the ATP7B variant spectrum between the siblings of each family. However, the siblings of both the families were found to harbor mutually exclusive pathogenic variants in suspected modifier genes implicated in copper metabolism and/or other neurological and hepatic disorders having overlapping symptoms with WD, viz., CFTR, PPARG, ABCB11, ATP7A, CYP2D6, mTOR, TOR1A, and CP, which can potentially explain their differential clinical phenotypes.
CONCLUSIONS: Clinical heterogeneity between siblings with WD with the same ATP7B mutation profile may be attributed to the presence of different pathogenic variants in potential modifier genes.

Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome (HADDTS) is an exceptionally rare disorder resulting from a heterozygous variant in the C-terminal binding protein 1 (CTBP1) gene. To date, a mere two variants (14 patients) have been documented on a global scale. The aim of this study was to identify a causative CTBP1 variant in a Chinese patient, and to determine the potential pathogenicity of the identified variant. Here, Whole-exome sequencing (WES) was conducted on the proband to pinpoint the candidate variant. Following this, Sanger sequencing was employed to validate the identified candidate variant and examine its co-segregation within the available family members. Employing both in silico prediction and three-dimensional protein modeling, we conducted an analysis to assess the potential functional implications of the variant on the encoded protein. Our investigation led to the identification of a novel heterozygous variant in the CTBP1 gene, namely, c.371 C>T (p.Ser124Phe), in a Chinese patient. This case represents the first confirmed instance of such a variant in a Chinese patient. When comparing the patient\'s clinical symptoms with those reported in the literature, notable distinctions were observed between her primary symptoms and those associated with HADDTS. She showed other signs such as microcephaly, coarse facial features, single transverse palmar crease, visible beard, myopia, coarse toenail and skeletal anomalies. This study enriching the spectrum of genetic variants observed in different ethnic populations and expanding the phenotypic profile associated with this gene. These findings are expected to contribute to the enhancement of future variant-based screening and genetic diagnosis, while also providing further insights into the pathogenic mechanisms underlying CTBP1-related conditions.

Chromosome 1p36 deletion accounts for around 1% of cases of intellectual disability. The pattern of clinical features includes developmental delay, hypotonia, seizures, short stature, intellectual disability, vision and hearing deficits, congenital heart disease, and renal abnormalities. The size of deletion can be variable. We report four cases of 1p36 deletion syndrome detected in the past 3 years in a genetic clinic. One patient was detected by next-generation sequencing, another by chromosomal microarray, and the remaining two by multiplex ligation-dependent probe amplification. We discuss the variable presentations in the four children. Early diagnosis enables better prognostication and further reproductive planning.

UNASSIGNED: Cerebrotendinous xanthomatosis is a disease with important clinical and molecular heterogeneity. CYP27A1 gene was described as the cause of these defects, with more than 50 mutations involved in the disease. The objective of this study was to carry out a genetic study and a clinical description of a patient with unusual clinical manifestation of the disease.
UNASSIGNED: DNA sequencing was used for the evaluation of CYP27A1 exon sequences and their intron/exon boundaries. Copy number variants were calculated using a method based on depth of sequencing coverage. In addition, the potential effects of the missense variants were analyzed, and an in-silico protein modeling tool was used. Finally, a patient case description was performed in order to evaluate patient phenotype according to genetic results.
UNASSIGNED: Patient clinical features indicate the possible presence of a disease milder phenotype. When analyzing the CYP27A1 gene, patient presents a pathogenic variant (p.Arg474Trp) and a variant of unknown significance (p.Met130Ile) that causes a slight modification of the protein functional structure. This variant in homozygosis or double or compound heterozygosis together with other biallelic pathological mutations may be the cause of the clinical phenotype observed in the reported patient.
UNASSIGNED: Clinical manifestations of cerebrotendinous xanthomatosis are heterogeneous, and sometimes wrongly suggest the presence of other diseases. Some patients seem to present an \"incomplete\" phenotype, which could be redefined as a variant of the disease with further studies. The evaluation of new mutations allows for earlier diagnosis and greater effectiveness in its treatment.