Single amino acid variation in MAB21L1 is dominantly associated with congenital eye defects

Microphthalmia¬†is a congenital eye defect caused by the underdevelopment of the optical structures typically bearing small eyeballs and cornea. We identified a novel missense variant in MAB21L1, which was dominantly inherited in a family with microphthalmia. We analyzed 3D structures of several mutant proteins predicted by AlphaFold2, and observed the effects of the mutant proteins […]

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Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders

In this work we analyzed the frequency, actionability and psychological impact of disclosing pathogenic variants in cancer susceptibility genes (CSG) as a secondary or incidental finding (SF/IF) mainly in pediatric patients. In a total of 533 exomes examined for non-cancer indications, we found a pathogenic variant in a CSG as a SF/IF in 2%. Around […]

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Experience of a 2-year spinal muscular atrophy NBS pilot study in Italy: towards specific guidelines and standard operating procedures for the molecular diagnosis

In the present article we report the results of the first Italian newborn screening project for Spinal Muscular Atrophy (SMA). The scenario of the disease has been revolutionized by three different effective treatments, acting at the molecular defect level, that, even if are not the cure, have radically changed the course of the disease, especially […]

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UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2

Pathogenic variants in RAD51C, RAD51D, BRIP1 are established ovarian cancer predisposition genes. PALB2 is firmly recognised as a breast cancer predisposition gene and more recently associated with ovarian cancer.¬† An association of RAD51C and RAD51D with breast cancer predisposition was recently confirmed. Whilst improved cancer risks estimates for these genes are available, to date no […]

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Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1

As common genetic testing methodologies cannot detect copy-neutral rearrangements such as inversions, this category of variant suffers from under-ascertainment. Pagnamenta and colleagues scanned data from the 100KGP (#genomes100k) for 43 genes linked to skeletal disorders. Ten individuals from 3 families harboured diagnostic inversions. In two families, GLI3-disrupting inversions segregated with skeletal features consistent with Greig […]

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X-linked variations in SHROOM4 are implicated in multiple congenital anomalies of the urinary tract, the anorectal, the cardiovascular, and the central nervous system

So far, variants in SHROOM4 have been associated with Stocco dos Santos syndrome, a neurodevelopmental disorder. Our report expands the clinical spectrum related to SHROOM4 variation: We identified single nucleotide variants and microdeletions in SHROOM4 in six individuals from four families, presenting with congenital anomalies of the urinary tract, the anorectum, the heart, and the […]

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Homozygous truncating variant in MAN2A2 causes a novel congenital disorder of glycosylation with neurological involvement

Golgi enzymes involved in N-glycan processing are critical for brain development, deficiencies in many leads to congenital disorders of glycosylation (CDG) with multisystem effects, particularly affecting the brain. Our study presents the first report of pathogenic variants in MAN2A2, causing a novel autosomal recessive CDG with neurological involvement. We identified a multiplex consanguineous family with […]

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Indepth characterization of a cohort of individuals with missense and loss-of-function variants disrupting FOXP2

Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported. We phenotyped 28 individuals from 17 families with pathogenic FOXP2-only variants. Speech disorders were prevalent into adulthood; with CAS the most common diagnosis. Cognition (average to mildly impaired) was incongruent […]

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The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2

Women with inherited BRCA1/2 gene alterations are at high risk of ovarian cancer, so usually opt for surgery to remove their ovaries and tubes. Many women delay surgery to complete families or avoid premature menopause. This study confirmed previous research showing that a 4-monthly blood test can detect ovarian cancer at earlier stages, resulting in […]

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