Clinical and molecular characterization of the first familial report of 1p32 microdeletion

Structural rearrangements of chromosome band 1p31p32 are rare, and their phenotypic consequences remain poorly delineated. Up to 12 patients with learning difficulties, developmental delay, multiple congenital anomalies and microdeletion of the chromosome band 1p31p32 have been described. Inheritance of this deletion has not been reported previously. We describe the inheritance of the 1p32 deletion and discuss the relevance of this deletion to the described phenotype. The differences in clinical and molecular characteristics between the proband and other published reports are reviewed. Patients were evaluated in OI-Genetics Clinic with history, examination and investigation. The existing literature on interstitial deletions of 1p was reviewed. Here, we report on a three-generation family, where the index patient was an adult female with learning difficulty, dysmorphic features, microcephaly, ambiguous genitalia, congenital hip dislocation and brachydactyly in whom a maternally inherited 1.45 Mbp interstitial deletion was detected at 1p32.3. Both her mother and maternal grandmother have learning difficulties and dysmorphic features. There are 14 OMIM genes in the deleted region including LRP8 and DMRTB1. The NFIA gene is not deleted in this family. The first report of a familial 1p32 microdeletion in three generations of a family carrying the smallest reported a deletion involving this region and brachydactyly as a previously unreported feature

Familial Bainbridge-Ropers syndrome: report of familial ASXL3 inheritance and a milder phenotype

De novo truncating and splicing pathogenic variants in the Additional Sex Combs-Like 3 (ASXL3) gene are known to cause neurodevelopmental delay, intellectual disability, behavioral difficulties, hypotonia, feeding problems and characteristic facial features. We previously reported 45 patients with ASXL3-related disorder including three individuals with a familial variant. Here we report the detailed clinical and molecular characteristics of these three families with inherited ASXL3-related disorder. First, a father and son with c.2791_2792del p.Gln931fs pathogenic variant. The second, a mother, daughter and son with c.4534C > T, p.Gln1512Ter pathogenic variant. The third, a mother and her daughter with c.4441dup, p.Leu1481fs maternally inherited pathogenic variant. This report demonstrates intrafamilial phenotypic heterogeneity and confirms heritability of ASXL3-related disorder

Exploring the association between SRPX2 variants and neurodevelopment: How causal is it?

The SRPX2 gene (Sushi-repeat-containing protein, X-linked, 2, OMIM*300642), located on Xq22.1, encodes a secreted protein that is highly expressed in neurons of cerebral cortex. SRPX2 was first implicated in neurodevelopment, learning and rolandic seizure when two patients with potentially pathogenic variants, c.980A>G (p.Asn327Ser) and c.215A>C (p.Tyr72Ser), in SRPX2 gene were identified. Subsequent experimental studies demonstrated that SRPX2 is needed for vocalization and synapse formation in mice, and that both silencing SRPX2 and injecting (p.Asn327Ser) in mouse models results in alteration in neuronal migration in cerebral cortex and epilepsy. A number of studies demonstrated that SRPX2 interacts with FOXP2 (Foxhead box protein P2), a gene responsible for speech and language disorder, and that FoxP2 controls timing and level of expression of SRPX2. Despite the supportive evidence for the role of SRPX2 in speech and language development and disorders, there are questions over its definitive association with neurodevelopmental disorders and epilepsy. In this paper, the role of SRPX2 as one in a network of many genes involved in speech and language is discussed. The goal of this paper is to examine the role of SRPX2 variants through describing two patients with potentially pathogenic variants in SRPX2, c.751G>C (p.Ala251Pro) and c.762G>T (p.Lys254Asn) presenting with language and motor delay, intellectual disability as well as congenital anomalies. We explore the contribution of SRPX2 variants to clinical phenotype in our patients and conclude that these variants at least partially explain the phenotype. Further studies are necessary to establish and confirm the association between SRPX2 and neurodevelopment particularly speech and language development

Expanding the molecular basis and phenotypic spectrum of ZDHHC9-associated X-linked intellectual disability

Pathogenic variants in Zinc Finger DHHC-Type Containing 9 (ZDHHC9) gene have been identified as the cause of X-linked intellectual disability (XLID) in a small number of families. There are a total of 11 reported pathogenic variants in ZDHHC9 in the literature. The majority of reported variants are familial point mutations. There is one report of XLID associated with a de novo mutation in ZDHHC9, and one family with intragenic deletion within ZDHHC9 detected by array CGH. Although initial reports of families with ZDHHC9 pathogenic variants suggested a nonsyndromic XLID, more recent reports suggest a syndromic phenotype with facial dysmorphism. Here we report four patients with pathogenic variants in ZDHHC9, a family with two siblings and their maternal uncle who presented with XLID due to intragenic deletion of ZDHHC9 detected by array CGH and an 11-year-old boy with a de novo pathogenic missense variant in ZDHHC9, which is the first recurrent ZDHHC9 mutation. Our patients had some distinctive facial features in common, including elongated and down-slanting palpebral fissures and high hairline. Marfanoid habitus and seizures that have been previously reported in association with pathogenic variants in ZDHHC9 were absent in our cohort. Clinical information on patients with ZDHHC9-associated XLID is very scarce. New reports of families with detailed clinical description will add to the existing knowledge and help understand the condition better

Mosaicism in ASXL3-related syndrome : description of five patients from three families

De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30–35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome

Aortic aneurysm/dissection and osteogenesis imperfecta: Four new families and review of the literature.

Osteogenesis imperfecta (OI) is the commonest form of heritable bone fragility. It is mainly characterized by fractures, hearing loss and dentinogenesis imperfecta. OI patients are at increased risk of cardiovascular disease of variable severity. Aortic aneurysm/dissection is one of the rarer but potentially serious cardiovascular complications of OI. So far, only six patients with aortic dissection and OI have been reported. As such, present OI diagnostic guidelines do not recommend systematic screening of patients for aortopathy. Here, we report on the clinical and molecular characteristics of three new OI patients and one additional patient with a first degree relative who presented with aortic dissection and/or aneurysm surgery. This observation further opens up the discussion on the need for and extent of cardiovascular screening in adult patients with OI

SDHC phaeochromocytoma and paraganglioma: A UK‐wide case series

Objective Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. Design This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. Patients Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. Measurements Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. Results We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11–79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79–0.99) in probands, and 0.16 (CI: 0–0.31) in non-probands, respectively. Conclusions This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance