Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome

Keser, Vafa; Lachance, Jean-François Boisclair; Alam, Sabrina; Lim, Youngshin; Scarlata, Eleonora; Kaur, Amarjot; Zhang, Tian Fang; Lv, Shunzeng; Lachapelle, Pierre; O’Flaherty, Cristián; Golden, Jeffrey A.; Jerome-Majewska, Loydie A.

doi:10.1038/s42003-019-0601-5

Cited by 13 publications

(12 citation statements)

References 32 publications

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“…This is supported by Snap29-deficient mouse models, suggesting that genetic or nongenetic modifiers affect skin findings. 13 The lack of dermatologic findings in these patients can mislead clinicians who may fail to test for SNAP29 variants. Furthermore, only a few of the recently reported patients had PMG or neuropathy typical of CEDNIK syndrome, although neuropathy has not been systematically evaluated.…”

Section: Discussionmentioning

confidence: 99%

“…In human skin and animal models, loss of SNAP29 leads to abnormal maturation, spatial organization, and differentiation of epidermal layers, neurons, and muscle fibers. 1,[10][11][12][13] CEDNIK syndrome is characterized by severe neurologic abnormalities leading to global developmental delay, hypotonia, and neuropathy as well as dermatologic abnormalities (ichthyosis and keratoderma). Typical MRI findings are hypoplasia/dysplasia of the corpus callosum and polymicrogyria (PMG).…”

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confidence: 99%

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New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

et al. 2021

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ObjectiveTo report 6 new patients with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome.MethodsClinical exome or targeted sequencing were performed to elucidate the molecular genetic cause in patients with neurocognitive abnormalities and brain imaging findings.ResultsCEDNIK syndrome is a rare genetic condition caused by biallelic pathogenic loss-of-function variants in synaptosomal-associated protein 29 (SNAP29), which encodes a vesicular membrane fusion protein. Clinical manifestations include significant developmental delay/intellectual disability (DD/ID), brain abnormalities, failure to thrive, and skin abnormalities. To date, 19 patients from 10 unrelated families with CEDNIK syndrome have been reported. We report 5 additional patients with homozygous predicted loss-of-function variants in SNAP29 and one with compound heterozygous variants: a frameshift SNAP29 variant and a 370 kb deletion on 22q11.2. All patients exhibit DD/ID, ichthyosis and/or palmoplantar keratoderma, and hypotonia. Four of 6 subjects had hypomyelinated white matter on MRI, 2 of 6 had early puberty, and 4 of 6 had strabismus, which were previously rarely reported. Other phenotypes were variably present, including dysmorphic features, feeding difficulties, and recurrent respiratory infections. The cohort includes 2 siblings with a c.2T>C variant who have a relatively milder phenotype, a patient with the most C-terminal variant yet described (c.622G>T), and 3 patients with previously described variants (c.354dupG, c.487dupA).ConclusionsThis cohort of 6 additional patients expands the genotypic and phenotypic spectrum of CEDNIK syndrome, highlighting previously under-recognized features such as hypomyelination, seizures, and early puberty. Owing to reduced penetrance of the skin phenotype, cerebral dysgenesis, and neuropathy, we propose renaming this syndrome SNAP29-related disorder.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

et al. 2021

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“…Mutations in SNAP29 result in variable expressivity and incomplete penetrance. Patients with homozygous mutations in SNAP29 are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome [ 21 ], which has a number of clinical manifestations, some of which overlap with those found in 22q11.2 deletion syndrome. SNAP29 was reported to be abnormal in 90% of patients with 22q11.2 deletion syndrome.…”

Section: Discussionmentioning

confidence: 99%

Identifying of 22q11.2 variations in Chinese patients with development delay

et al. 2021

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Background 22q11.2 variation is a significant genetic factor relating to development delay and/or intellectual disability. However, the prevalence, genetic characteristics and clinical phenotype in Chinese patients are unknown. Methods In total 6034 patients with development delay and/or intellectual disability were screened by multiplex ligation-dependent probe amplification (MLPA) P245 and G-band karyotyping. The positive patients with 22q11.2 imbalance were confirmed by MLPA P250 assay. Results 52 (0.86%) patients were found to carry different levels of 22q11.2 variations, in which 37 cases (71.2%) had heterozygous deletions, whereas 15 (28.8%) had heterogeneous duplications. 34 cases (65.4%) carried typical imbalance from low copy repeat (LCR) 22 A to D. The other cases had atypical variations, relating to LCR22 A-B, LCR22 C-D, LCR22 B-D, LCR22 D-E, LCR22 E-F and LCR22 B-F region. The phenotypes of these 52 patients were variable, including development delay, language delay, facial anomalies, heart defects, psychiatric/behavior problems, epilepsy, periventricular leukomalacia, hearing impairment, growth delay etc. Conclusion These data revealed the prevalence and variability of 22q11.2 genomic imbalance in Chinese patients with development delay and/or intellectual disability. It suggested that genetic detection of 22q11.2 is necessary, especially for the patients with mental retardation and development disorders, which deserves the attention of all pediatricians in their daily work.

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“…Snap29-/- mutant male mice have a significantly reduced testis/body ratio, abnormal spermatogenesis, and no live births were found in the offspring. This indicated that SNAP29 is essential for male fertility and spermatogenesis [ 45 ]. Other study also indicated that patients with typical LCR22 A-D deletions may present with cryptorchidism [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature

Chen

Yang

et al. 2022

BMC Endocr Disord

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Background 22q11.2 deletion syndrome (DiGeorge syndrome) is associated with multiple organ dysfunctions such as cardiac defects, immunodeficiency, and hypoplasia of parathyroid glands. Moreover, the phenotype of 22q11.2 DS has clinical variability and heterogeneity. Case presentation In this report, we present the case of a 35-year-old patient with a past medical history that included recurrent infections, mild learning difficulties in childhood, pediatric obesity, and cataract. He was admitted to the endocrinology department for the management of hypogonadism and hypocalcemia. During the 3-year follow-up, the patient gradually developed primary hypoparathyroidism, hypogonadism, chronic renal failure, and heart failure, and his medical condition deteriorated. Meanwhile, in order to improve clinicians’ awareness of the endocrine manifestations of adult 22q11.2 DS and reduce missed diagnoses, we reviewed 28 case reports of adult 22q11.2 DS to analyze the clinical characteristics. Discussion Here, we report the case of a young man diagnosed with 22q11.2 DS presented a rare combination of multiple endocrine disorders. This is the first time that a patient with 22q11.2DS had late-onset hypogonadism caused by primary testicular failure combined with decreased pituitary gonadotropin reserve in a patient with 22q11.2DS.

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Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome

Cited by 13 publications

References 32 publications

New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

New Cohort of Patients With CEDNIK Syndrome Expands the Phenotypic and Genotypic Spectra

Identifying of 22q11.2 variations in Chinese patients with development delay

Hypoparathyroidism and late-onset hypogonadism in an adult male with familial 22q11.2 deletion syndrome: a case report with 3-year follow-up and review of the literature

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