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Background: Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability., Results: The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive., Conclusions: Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.

Background: Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy., Case Presentation: The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy., Conclusions: Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

Background: The discovery of disease pathogenesis requires systematic agnostic screening of multiple homeostatic processes that may become deregulated. We illustrate this principle in the evaluation and diagnosis of a 5-year-old boy with Joubert syndrome type 10 (JBTS10). He carried the OFD1 mutation p.Gln886Lysfs*2 (NM_003611.2: c.2656del) and manifested features of Joubert syndrome., Methods: We integrated exome sequencing, MALDI-TOF mass spectrometry analyses of plasma and cultured dermal fibroblasts glycomes, and full clinical evaluation of the proband. Analyses of cilia formation and lectin staining were performed by immunofluorescence. Measurement of cellular nucleotide sugar levels was performed with high-performance anion-exchange chromatography with pulsed amperometric detection. Statistical analyses utilized the Student's and Fisher's exact t tests., Results: Glycome analyses of plasma and cultured dermal fibroblasts identified abnormal N - and O -linked glycosylation profiles. These findings replicated in two unrelated males with OFD1 mutations. Cultured fibroblasts from affected individuals had a defect in ciliogenesis. The proband's fibroblasts also had an abnormally elevated nuclear sialylation signature and increased total cellular levels of CMP-sialic acid. Ciliogenesis and each glycosylation anomaly were rescued by expression of wild-type OFD1 ., Conclusions: The rescue of ciliogenesis and glycosylation upon reintroduction of WT OFD1 suggests that both contribute to the pathogenesis of JBTS10.