Clinical Genetics

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF...

ASXL3-related disorder, sometimes referred to as Bainbridge-Ropers syndrome, was first identified as a distinct neurodevelopmental disorder by Bainbridge et al. in 2013. Since then, there have been a number of case series and single case reports published worldwide. A comprehensive review of the literature was carried out. Abstracts were screened, relevant literature was analysed, and descriptions of common phenotypic features were quantified. ASXL3 variants were collated and categorised. Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%)...

Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia, and Cardiac defects (PDAC) syndrome is a genetically heterogeneous multiple congenital malformation syndrome. Although pathogenic variants in RARB and STRA6 are established causes of PDAC, many PDAC cases remain unsolved at the molecular level. Recently, we proposed biallelic WNT7B variants as a novel etiology based on several families with typical features of PDAC syndrome albeit with variable expressivity. Here, we report three patients from two families that share a novel founder variant in WNT7B (c...

Chromosome 22q13.3 deletion (Phelan-McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS-SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS-SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression...

Considering the high prevalence and poor prognosis of cardiometabolic multimorbidity (CMM), identifying causal factors and actively implementing preventive measures is crucial. However, Mendelian randomization (MR), a key method for identifying the causal factors of CMM, requires knowledge of the effects of SNPs on CMM, which remain unknown. We first analyzed the genetic overlap of single cardiometabolic diseases (CMDs) using the latest genome-wide association study (GWAS) for evidential support and comparison...

Spastic paraplegia type 4 (SPG4), caused by SPAST mutations, is the most predominant subtype of hereditary spastic paraplegia. Most documented SPG4 patients present as pure form, with the complex form rarely reported. We described the clinical and genetic features of 20 patients with complex phenotypes of SPG4 and further explored the genotype-phenotype correlations. We collected detailed clinical data of all SPG4 patients and assessed their phenotypes. SPAST gene mutations were identified by Multiplex ligation-dependent probe amplification in combination with whole exome sequencing...

Low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor of the Wnt signaling pathway, which plays an essential role in various biological activities during embryonic and postnatal development. LRP6 is exceptionally associated with rare diseases and always with autosomal dominant inheritance. Here we report a familial phenotype of high bone mass associated with skeletal anomalies and oligodontia but also persistent left superior vena cava, inguinal hernia, hepatic cysts, abnormal posterior fossa and genital malformations...

Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems...

A case of mosaic MTOR-associated hemimegalencephaly and hypomelanosis of Ito, died at 33 probably because of sudden unexpected death in epilepsy. Assessment of the variant allele fraction (VAF) in different tissues postmortem showed high variability not correlated with clinical features, representing the most detailed assessment of VAFs in different tissues to date.

Skeletal dysplasias (SKDs) are a heterogeneous group of more than 750 genetic disorders characterized by abnormal development, growth, and maintenance of bones or cartilage in the human skeleton. SKDs are often caused by variants in early patterning genes and in many cases part of multiple malformation syndromes and occur in combination with non-skeletal phenotypes. The aim of this study was to investigate the underlying genetic cause of congenital SKDs in highly consanguineous Pakistani families, as well as in sporadic and familial SKD cases from India using multigene panel sequencing analysis...

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022)...

Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled-4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock-down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled-4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants...

Biallelic disease-causing variants in the ALPK3 gene were first identified in children presenting with a severe cardiomyopathy. More recently, it was shown that carriers of heterozygous ALPK3 null variants are at risk of developing hypertrophic cardiomyopathy (HCM) with an adult onset. Since the number of reported ALPK3 patients is small, the mutational spectrum and clinical data are not fully described. In this multi-centric study, we described the molecular and clinical spectrum of a large cohort of ALPK3 patients...

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals...

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies...

A 5-year-old affected male had following phenotypes: autism, motor stereotypy, developmental regression, staring gaze, absent speech, and behavioral abnormality. The biochemical testing was normal and genetic testing identified a de novo pathogenic variant in ITSN1 gene in the proband. To our knowledge, this is the second report that elucidates the role of ITSN1 gene in an autosomal dominant neurodevelopmental disorder.

Oligoasthenoteratozoospermia (OAT) is a common type of male infertility; however, its genetic causes remain largely unknown. Some of the genetic determinants of OAT are gene defects affecting spermatogenesis. BCORL1 (BCL6 corepressor like 1) is a transcriptional corepressor that exhibits the OAT phenotype in a knockout mouse model. A hemizygous missense variant of BCORL1 (c.2615T > G:p.Val872Gly) was reported in an infertile male patient with non-obstructive azoospermia (NOA). Nevertheless, the correlation between BCORL1 variants and OAT in humans remains unknown...

Psychiatric genetic counseling (pGC) can improve patient empowerment and self-efficacy. We explored the relationship between pGC and psychiatric hospitalizations, for which no prior data exist. Using Population Data BC (a provincial dataset), we tested two hypotheses: (1) among patients (>18 years) with psychiatric conditions who received pGC between May 2010 and Dec 2016 (N = 387), compared with the year pre-pGC, in the year post-pGC there would be fewer (a) individuals hospitalized and (b) total hospital admissions; and (2) using a matched cohort design, compared with controls (N = 363, matched 1:4 for sex, diagnosis, time since diagnosis, region, and age, and assigned a pseudo pGC index date), the pGC cohort (N = 91) would have (a) more individuals whose number of hospitalizations decreased and (b) fewer hospitalizations post-pGC/pseudo-index...

The genetic risk of chronic diseases represents a complex medical setting in which individuals need to adapt to health conditions that manage daily living towards to healthy behaviours. This exploratory review focused on psychological counselling for genetic risk diagnosis. This study aimed to address the psychological management of the impact of genetic risk on chronic diseases. We performed a systematic search of MEDLINE via PubMed, Embase, Web of Science, PsycINFO and Scopus for articles from May 2012 to August 2023...

The RREB1 is a zinc finger transcription factor that plays a role in regulating gene expression and inactivating MAPK signalling components. To date, no pathogenic variant in the RREB1 gene has been associated with any disease, but several cases of 6p terminal deletions affecting the RREB1 gene have been reported. In this study, we report the first case of RREB1-associated Noonan-like RASopathy caused by a pathogenic variant within this gene. Genetic testing included whole-genome sequencing (WGS) of the proband and Sanger sequencing of the proband, his parents, and his sibling...