European journal of medical genetics最新文献

Over two decades ago, a primigravid female presented with concern for recurrence of an adverse phenotype affecting her three brothers. The three brothers presented with intellectual disability, developmental delay, behavior problems and dysmorphic features. The screening tools available at the time revealed an FGD1 variant present in all three brothers, their mother being a carrier, absent in their unaffected uncle, and absent in the proband herself. This variant was hypothesized to be explanatory, but years later more advanced genetic screening showed that it was benign. Episign analysis revealed the true cause, a novel pathogenic KDM5C variant. This case study provides further insight into the KDM5C phenotype and demonstrates the importance of amending past errors as science evolves.

Biallelic loss-of-function variants in STRC contribute to mild-moderate hearing loss (DFNB16). Here, we report a female patient with mild hearing loss. Exome sequencing and MLPA analysis revealed STRC biallelic inactivation due to a nonsense and a CKMT1B-STRC deletion. Analysis of the self-reported normal-hearing parents revealed inconsistent Mendelian inheritance. Indeed, the mother was a heterozygous carrier of a CKTM1B-STRC-CATSPER2 deletion, and the father shared the same genotype as his daughter. He was later found to also have mild-moderate hearing loss. To address these discrepancies, we used long-read sequencing and optical genome mapping. We demonstrated that the father, in fact, carried a CKMT1B-STRC-CATSPER2 deletion in trans with the STRC nonsense variant and a tandem duplication of CATSPER2-CKMT1A. The proband inherited this latter haplotype, together with the maternal CKMT1B-STRC-CATSPER2 deletion. Combining these two technologies allowed us to fully elucidate the complex structural rearrangements at the STRC locus and provide appropriate genetic counselling.

The Chromodomain Helicase DNA-binding (CHD) protein family is ATP-dependent chromatin remodeling proteins that utilize energy produced by ATP hydrolysis to regulate chromatin structure and thereby modulate gene expression. The earliest report of a CHD3 gene mutation was by O'Roak, who found it during whole exome sequencing of 189 autism families in 2012. In 2018, Snijders Blok systematically assessed the autosomal dominant neurodevelopmental disorder caused by CHD3 gene damage, known as Snijders Blok-Campeau syndrome (SNIBCPS, OMIM 618205). Its typical features include global developmental delay, speech delay, mild to severe intellectual disability, hypotonia, autism, and distinctive facial features such as macrocephaly (microcephaly in minority), prominent forehead and so on. This article reports a patient of slow speech, intellectual disability, epilepsy, spastic paraplegia, ataxia and situs inversus with a CHD3 gene mutation. The features of spastic paraplegia, ataxia, and situs inversus have not been reported previously. In conclusion, CHD3 gene mutations represent a rare disease with diverse clinical phenotypic features. This patient contributes valuable insights into the understanding of CHD3 gene mutation manifestations, expanding the scope beyond previously reported features.

Congenital Heart Defect and Ectodermal Dysplasia (CHDED) is an autosomal dominant disorder caused by the PRKD1 gene. CHDED is characterized by heart defects and ectodermal dysplasia. To date, eight patients with CHDED have been described. Calcifications were present in three patients with CHDED. (two patients; renal calcifications, one patient; brain calcifications). The organ distribution of calcifications in CHDED has been unclear. We report here another patient with CHDED and brain calcifications. The patient was a 9-month-old Japanese girl. She presented with heart defects and ectodermal dysplasia. At 6 months of age, she had generalized seizures, and a CT scan revealed calcifications in the bilateral deep cerebral white matter. The seizures resolved with the administration of levetiracetam. The patient had a de novo, heterozygous pathogenic variant, c.1808G > A, p.(Arg603His), in the PRKD1 gene. Together with the previously reported patients mentioned above, we demonstrated the role of the PRKD1 variant in brain calcification. We propose that PRKD1 and two genes, ITGB2 and JAM2, which are known to be associated with brain calcification, act through a common signaling pathway abnormality. In support of our hypothesis, there are some experimental results that link PRKD1 and JAM2. PRKD1 functions with the integrin ITGB2 as a partner. JAM2, which is associated with brain calcification and is critical for maintaining of the tight junction of the endothelial cells, interacts with integrins including ITGB2. Therefore, PRKD1 could lead to the pathological phenotype of brain calcification.

Genetic Counselling Supervision (GCS) plays an integral role in professional development, stimulating reflective practice and helping to prevent burnout. Nevertheless, evidence points to insufficient practice of GCS. This study aimed to explore the current state of counselling supervision access during MSc training, along with barriers and facilitators for its implementation. MSc coordinators of the current EBMG accredited programmes were invited to participate in this study via email, with the request to fill out a questionnaire. The qualitative data obtained was reviewed using thematic analysis, while descriptive statistics was used for the quantitative data. GCS was considered crucial for fostering professional development, safe practice, and emotional support for the future professionals. While all MSc programmes included counselling supervision in their course curricula, its implementation was highly heterogeneous. Students have access to GCS during clinical placements in 62,5% of the programmes, facilitated by institutional support and EBMG guidelines. Several barriers hindered its broader implementation, as was the case of a shortage of senior genetic counsellors and the lack of professional recognition in some countries. This study compiled evidence of the insufficient practice of GCS across Europe and its limited integration in MSc programmes. Therefore, we recommend educational pathways actively promote genetic counselling supervision routines to ensure graduates enter the workforce with the necessary tools to provide care with the expected standard of safety and quality, while maintaining a reflective practice.

Shprintzen-Goldberg syndrome is a rare systemic connective tissue disorder caused by heterozygous mutations in the Sloan-Kettering Institute (SKI) gene. The clinical presentation is reminiscent of Marfan and Loeys-Dietz syndromes, making differential diagnosis challenging. Shprintzen-Goldberg syndrome's distinctive features are craniosynostosis and learning disabilities. The pathophysiology of these three conditions is similar as they all result in the deregulation of the transforming growth factor beta (TGF-β) signaling pathway and thus an altered expression of TGF-β responsive genes. We report a family of two patients: one with initial suspicion of hypermobile Ehlers-Danlos syndrome and the second with suspicion of Marfan syndrome, as the Marfan systemic score was positive and no craniosynostosis or learning disabilities were described. They were diagnosed with Shprintzen-Goldberg syndrome after a heterozygous probably pathogenic variant in the second mutational hotspot of SKI Dachshund homology domain was identified. We reviewed the genotype-phenotype correlation among the three mutational hotspots in SKI: the amino acids 20 to 35 of the receptor-regulated small mothers against decapentaplegic domain (group 1, n = 32), amino acids 94 to 117 of Dachshund homology domain (group 2, n = 12), and threonine 180 of Dachshund homology domain (group 3, n = 11 including our patients). As the main differential diagnoses of Shprintzen-Goldberg syndrome are Marfan and Loeys-Dietz syndromes, we completed the comparison already made by Loeys and Dietz. (2008) of Shprintzen-Goldberg syndrome clinical features among the different mutational hotspots with Marfan syndrome and the different types of Loeys-Dietz syndrome. In addition to the already described absence of learning disabilities in Shprintzen-Goldberg patients with a pathogenic variant in the threonine 180 of Dachshund homology domain, facial features also appeared to be less severe. The clinical overlap with Marfan and Loeys-Dietz patients requires genetic testing in order to establish an accurate molecular diagnosis at the variant level, and to adapt genetic counseling and clinical management.

Background: The Roma population are an endogamous, genetically isolated, minority population who migrated from North-Western India to Europe from the 10th Century throughout the Byzantine period and continues to the present day. Approximately 10-12 million Romani people reside in segregated settlements in Europe, and smaller populations live in North America and China. In addition to the endogamy, they also practice consanguinity. This has resulted in a higher frequency of rare autosomal recessive disorders some of which are unique to the Roma population. Some disorders result from founder variants whilst others are private variants, occurring within one nuclear family. Most are found as homozygous variants but compound heterozygosity is seen in a number of conditions.

Objective: Clinicians and scientists with experience in managing and diagnosing rare diseases in this population in Ireland, Romania and Greece have developed a comprehensive catalogue of autosomal recessive inherited disorders found in the Roma population. Our aim is that this catalogue will aid rapid diagnosis and highlight the differential diagnoses to consider in challenging cases.

Methods: We performed a detailed literature search to identify relevant publications and disease variants described in patients whose ethnicity was described as Roma. In addition, we interrogated data from local clinicians and colleagues in Ireland and Romania to collect additional unpublished variants which have yet to be reported in the medical literature. Where possible, we have mapped these disorders back to their European country of origin. Furthermore, we searched the variants allele frequencies on ClinVar. We analysed exome data from New Delhi, India to trace any of these founder variants back their origins.

Results: We identified 90 distinct autosomal recessive disorders, manifesting as 91 distinct phenotypes and 111 pathogenic disease variants. These include both published (n = 91) and unpublished (n = 20) findings identified in the Roma population in Europe. The Indian exome data revealed that only 12/111 variants were identified.

Conclusion: We have assembled a catalogue of inherited autosomal recessive disorders and 111 pathogenic variants found in the Roma population. We hope that this will assist the medical and scientific community to make prompt diagnoses and consider adaptation of a targeted genetic approach to facilitate timely and cost-effective diagnoses in this population.

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant neurodevelopmental disorder mainly characterized by global development delay/intellectual disability, white matter abnormalities, and behavioral manifestations. It is caused by pathogenic variants in the KMT2E gene. Here we report seven new patients with loss-of-function KMT2E variants, six harboring frameshift/nonsense changes, and one with a 7q22.3 microdeletion encompassing the entire gene-locus. We further characterize both the clinical phenotype as well as its associated pathogenic variants' spectrum providing new information on sex-related phenotype distribution, according to the variant groups. We also highlight different epilepsy phenotype-genotype correlation with preferential association of generalized epilepsy and/or developmental and epileptic encephalopathy with missense pathogenic variants and focal epilepsy, childhood absence epilepsy and/or febrile seizures with pathogenic truncating variants and structural rearrangements. By a systematic review of the previously reported series, we also discuss previously unappreciated findings, including progressive macrocephaly, apraxia, and higher risk of bone fractures.

Background: Ulnar mammary syndrome (UMS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in the T-box transcription factor 3 (TBX3) gene. The phenotype is classically characterized by upper limb defects and apocrine/mammary gland hypoplasia. Endocrine abnormalities include hypogonadotropic hypogonadism (HH), partial growth hormone deficiency and dysmorphic features, while ectopic pituitary gland and various congenital anomalies have also been described. Here, we report a family with a unique clinical presentation.

Methods: Exome sequencing was performed for twin siblings with micropenis, neonatal hypogonadism, and congenital giant bladder diverticula.

Results: We identified a novel likely pathogenic heterozygous TBX3 variant c.844G>T; p.(Gly282Cys) inherited from the apparently unaffected mother. Reverse phenotyping confirmed that the mother and the twins had features suggestive of UMS spectrum. The mother had been diagnosed as having HH, with an hypoplastic pituitary gland. The physical examination revealed a bifid nasal tip and a bi-lobulated tongue tip typical for UMS with no apparent limb or mammary defects.

Discussion: This report extends the phenotype of the TBX3-related disorder to include HH and bladder anomalies without significant limb or mammary manifestations.

Lissencephaly (LIS) is a subtype of malformations of cortical development (MCD), characterized by smooth brain surfaces and underdeveloped gyri and sulci. This study investigates the genetic cause of pachygyria in a Chinese male infant diagnosed with the condition, who previously showed no causative variant through trio whole exome sequencing (Trio-WES) and copy number variation sequencing (CNVseq). Whole-genome sequencing (WGS) was conducted, revealing a novel heterozygous inversion spanning 1.02M bps on chromosome 17 [seq[GRCh37]inv(17)(p13.3p13.2)|NC_000017.10:g.2562761_3581978inv] involving the PAFAH1B1 gene. This de novo variant, confirmed by PCR and Sanger sequencing, was present in the proband but absent in the parents. The inversion disrupts PAFAH1B1, classified as haploinsufficient in the ClinGen database, and is associated with lissencephaly-1 (LIS1) and subcortical band heterotopia (SBH) (OMIM #607432). The findings align with the known characteristics of this disorder, extending the understanding of the molecular mechanisms underlying pachygyria. This identification offers new insights for individuals with developmental delays and brain malformations to uncover the genetic cause of their conditions.