A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants

Mancini, Cecilia; Zonta, Andrea; Botta, Giovanni; Klobus, Andrea Breda; Valbonesi, Stefano; Pasini, Barbara; Giorgio, Elisa; Viora, E.; Brusco, Alfredo; Brussino, Alessandro

doi:10.1016/j.ejmg.2018.11.012

Cited by 5 publications

(5 citation statements)

References 21 publications

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“…Following genetic counseling, the couple opted for invasive prenatal testing in their next pregnancy, in which the fetus was an unaffected carrier of both conditions. This case provides additional information on the prenatal phenotype for SMOC1‐ related disorders with features in common with the prenatal phenotype previously reported 3 . The additional scan findings seen at 24 + 0 weeks were consistent with the diagnosis as bilateral severe micro/anophthalmia and limb anomalies were detected.…”

Section: Discussionsupporting

confidence: 83%

“…This case provides additional information on the prenatal phenotype for SMOC1-related disorders with features in common with the prenatal phenotype previously reported. 3 The additional scan findings seen at 24 þ 0 weeks were consistent with the diagnosis as bilateral severe micro/anophthalmia and limb anomalies were detected. The cross-fused left kidney seen in this case has not specifically been reported in affected individuals, although horseshoe kidneys have been seen on imaging in 4/8 probands with biallelic SMOC1 variants.…”

Section: Discussionsupporting

confidence: 57%

“…Biallelic pathogenic variants in SMOC1 are associated with microphthalmia with limb anomalies (MIM 206920) and prenatal presentations have been reported previously, with features including depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, clefting of the sacral and lower-lumbar vertebrae, and bilateral microphthalmia identified sonographically, with micrognathia, oligodactyly and tibial bowing identified after fetal autopsy. 3 The SMOC1 frameshift variant identified in this study is predicted to undergo nonsense-medicated decay causing loss of function, which is a known disease mechanism. This variant was also absent from the gnomAD population database, resulting in a pathogenic variant classification.…”

Section: Diagnostic Results and Interpretationmentioning

confidence: 88%

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A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2‐related congenital adrenal hyperplasia

Willison,

Ramachandran,

Chandler

et al. 2023

Prenatal Diagnosis

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Trio exome sequencing was performed on a fetus with bilateral mesomelia of the lower limbs with significant angulation of the tibial bones, micrognathia and hypertelorism detected on ultrasound scan at 19 + 0 weeks gestation. The couple is consanguineous. A homozygous pathogenic frameshift variant in the SMOC1 gene (c.339_340del p.(Phe114Cysfs*40)) was detected and both parents were shown to be heterozygous. Pathogenic variants in the SMOC1 gene are associated with microphthalmia with limb anomalies which multidisciplinary team discussion determined to be causal of the scan anomalies detected. The fetus was also a compound heterozygote for CYP21A2 pathogenic variants, confirming a second diagnosis of non‐classical congenital adrenal hyperplasia, which was felt incidental to the scan findings. The risk that this couple's next pregnancy would be affected by either of these disorders is 1 in 4 (25%) and demonstrates the importance of genetic diagnoses for the family and implications for future pregnancies.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 57%

Section: Diagnostic Results and Interpretationmentioning

confidence: 88%

See 1 more Smart Citation

A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2‐related congenital adrenal hyperplasia

Willison,

Ramachandran,

Chandler

et al. 2023

Prenatal Diagnosis

View full text Add to dashboard Cite

show abstract

“…5 It is caused by a biallelic pathogenic variant of the SMOC1 gene. 2 However, Rainger et al did not discover any SMOC1 anomalies in six typical families, indicating heterogeneity in the MLA locus. 3 Kondo et al discovered a homozygous FNBP4 mutation in a case of MLA by sequencing the entire exome.…”

Section: Discussionmentioning

confidence: 97%

“…1 It is caused by a biallelic pathogenic variant of the SMOC1 gene. 2 However, in some families with typical acromegaly syndrome, SMOC1 mutations cannot be identified, indicating limitations in existing SMOC1 mutation analysis. 3 , 4 We report a case of microphthalmia (anophthalmia) with limb anomalies and an interfrontal teratoma.…”

Section: Introductionmentioning

confidence: 99%

A 12 Week Fetus with Anophthalmia, Limb Anomalies and Infratemporal Teratoma

Lu,

Zhao,

2024

IJWH

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Background Microphthalmia is a rare autosomal recessive condition commonly known as Waardenburg anophthalmia syndrome (WAS) or oculo-acromal formation syndrome (MIM#206920). Case Description Here, we report the case of a woman whose fetal ultrasonography at 12 weeks of pregnancy revealed multiple fetal abnormalities. These included the absence of the left upper limb, an unclear display of the right orbit, a visible maxillary space, and a round, echoless appearance measuring 4 mm in diameter in the middle of the forehead. There was also a significant echo in the sac wall. The possibility of a frontal meningocele or a proboscis-like nose was considered. The fetus was delivered with absence of the left upper limb, absence of the right eye, a cleft lip on the right side, and a milky white sac with a diameter of 5 mm on the forehead after the pregnancy was terminated at the hospital. Pathological investigation revealed a mature cystic teratoma. The conclusion was microphthalmia with limb anomalies (MLA) after missing limbs, absence of eyes, and cleft lip were input into the Online Mendelian Inheritance in Man database. The case was diagnosed with fetal microphthalmia with limb anomalies and an interfrontal teratoma. Conclusion In this case, the entire exon analysis was not conducted, and as a result, the final diagnosis remains unclear. Based exclusively on the phenotype of the induced fetus, MLA was diagnosed. It is proposed that cases satisfying the requirements for a pathological diagnosis should undergo a pathological examination to establish a definitive diagnosis.

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SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation

Balcomb,

Johnston,

Kavanagh

et al. 2024

Acta Neuropathol

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SMOC1 has emerged as one of the most significant and consistent new biomarkers of early Alzheimer’s disease (AD). Recent studies show that SMOC1 is one of the earliest changing proteins in AD, with levels in the cerebrospinal fluid increasing many years before symptom onset. Despite this clear association with disease, little is known about the role of SMOC1 in AD or its function in the brain. Therefore, the aim of this study was to examine the distribution of SMOC1 in human AD brain tissue and to determine if SMOC1 influenced amyloid beta (Aβ) aggregation. The distribution of SMOC1 in human brain tissue was assessed in 3 brain regions (temporal cortex, hippocampus, and frontal cortex) using immunohistochemistry in a cohort of 73 cases encompassing advanced AD, mild cognitive impairment (MCI), preclinical AD, and cognitively normal controls. The Aβ- and phosphorylated tau-interaction with SMOC1 was assessed in control, MCI, and advanced AD human brain tissue using co-immunoprecipitation, and the influence of SMOC1 on Aβ aggregation kinetics was assessed using Thioflavin-T assays and electron microscopy. SMOC1 strongly colocalized with a subpopulation of amyloid plaques in AD (43.8 ± 2.4%), MCI (32.8 ± 5.4%), and preclinical AD (28.3 ± 6.4%). SMOC1 levels in the brain strongly correlated with plaque load, irrespective of disease stage. SMOC1 also colocalized with a subpopulation of phosphorylated tau aggregates in AD (9.6 ± 2.6%). Co-immunoprecipitation studies showed that SMOC1 strongly interacted with Aβ in human MCI and AD brain tissue and with phosphorylated tau in human AD brain tissue. Thioflavin-T aggregation assays showed that SMOC1 significantly delayed Aβ aggregation in a dose-dependent manner, and electron microscopy confirmed that the Aβ fibrils generated in the presence of SMOC1 had an altered morphology. Overall, our results emphasize the importance of SMOC1 in the onset and progression of AD and suggest that SMOC1 may influence pathology development in AD.

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A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants

Cited by 5 publications

References 21 publications

A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2‐related congenital adrenal hyperplasia

A novel SMOC1 pathogenic homozygous variant in a fetus with mesomelia of the lower limbs, micrognathia and hypertelorism and an incidental finding of CYP21A2‐related congenital adrenal hyperplasia

A 12 Week Fetus with Anophthalmia, Limb Anomalies and Infratemporal Teratoma

SMOC1 colocalizes with Alzheimer’s disease neuropathology and delays Aβ aggregation

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