Sedaghatian-type spondylometaphyseal dysplasia: Whole exome sequencing in neonatal dry blood spots enabled identification of a novel variant in GPX4

Background. Split-hand/foot malformation (SHFM) is a severe congenital disability mainly characterized by the absence or hypoplasia of the central ray of the hand/foot. To date, several candidate genes associated with SHFM have been identified, including TP63, DLX5, DLX6, FGFR1, and WNT10B. Herein, we report a novel variant of TP63 heterozygously present in affected members of a family with SHFM. Methods. This study investigated a Chinese family, in which the proband and his son suffered from SHFM. The peripheral blood sample of the proband was used to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Postsequencing bioinformatic analyses and Sanger sequencing were conducted to verify the identified variants and parental origins on all family members in the pedigree. Results. By postsequencing bioinformatic analyses and Sanger sequencing, we identified a novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in this family that results in a substitution of methionine with isoleucine, which is probably associated with the occurrence of SHFM. Conclusion. A novel missense variant (NM_003722.4:c.948G>A; p.Met316Ile) of TP63 in SHFM was thus identified, which may enlarge the spectrum of known TP63 variants and also provide new approaches for genetic counselling of families with SHFM.

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276 A new face for an old foe?

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-abn.140 ◽

2018 ◽

Vol 89 (10) ◽

pp. A40.3-A40 ◽

Cited By ~ 1

Author(s):

Sangha Gavinda ◽

Bron Anthony ◽

Donaghy Michael ◽

Evans Cerys ◽

Hardcastle Alison ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Family Members ◽

Calcium Sensitivity ◽

Actin Binding ◽

Cranial Neuropathy ◽

Limb Weakness ◽

Proteolytic Cascade ◽

Whole Exome ◽

Novel Variant

BackgroundMutations in the protein gelsolin result in hereditary systemic amyloidosis, characterised by onset of corneal lattice dystrophy in the third decade, a slowly progressive cranial neuropathy and cutis laxa. To date four dominantly inherited gelsolin mutations have been identified, two mutations resulting in the classical syndrome and two mutations resulting in renal-predominant amyloidosis.MethodsWe identified a family in which four individuals in three generations presented with corneal lattice dystrophy and neurological symptoms. Detailed clinical neurological and ophthalmological assessment and investigations including neurophysiology and imaging were performed. Whole exome sequencing was undertaken in three family members.ResultsWhole exome sequencing revealed a novel variant in the gelsolin gene (c. G1738A; p. E580K), dominantly inherited and predicted to be pathogenic. Examination, neurophysiological testing and imaging revealed the presence of distal upper limb weakness and wasting, corneal lattice dystrophy and cervical myelopathy in all affected family members.ConclusionThe E580K mutation described in this family is in a conserved calcium-sensitive actin-binding domain that displays sequence homology with other actin-depolymerising proteins. Mutations in this domain may result in abnormal gelsolin-actin interactions and changes in calcium sensitivity may render the protein susceptible to the same aberrant proteolytic cascade as with other known mutations.

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Whole-Exome Sequencing Identified a Novel Variant (C.405_422+39del) in DSP Gene in an Iranian Pedigree with Familial Dilated Cardiomyopathy

Reports of Biochemistry and Molecular Biology ◽

10.52547/rbmb.10.2.280 ◽

2021 ◽

Vol 10 (2) ◽

pp. 280-287

Author(s):

Yeganeh Eshaghkhani ◽

Arezoo Mohamadifar ◽

Mostafa Asadollahi ◽

Mahdieh Taghizadeh ◽

Arezou Karamzade ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Familial Dilated Cardiomyopathy ◽

Whole Exome ◽

Novel Variant

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A Novel Variant of SMARCB1 in Rare Familial Schwannomatosis Identified by Whole-Exome Sequencing and Genotype-Phenotype Correlation Analysis.

10.21203/rs.3.rs-1157679/v1 ◽

2021 ◽

Author(s):

Conghui Wang ◽

Yuqiong Chai ◽

Xuechao Zhao ◽

Qianqian Li ◽

Chen Chen ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Suppressor Gene ◽

Loss Of Function ◽

Phenotype Correlation ◽

Rhabdoid Tumour ◽

Whole Exome ◽

Mutation Database ◽

Novel Variant ◽

Autosomal Dominant Inheritance Pattern

Abstract Background: Variants in the tumor suppressor gene SMARCB1 could cause different conditions. In some cases, germline and somatic variants in SMARCB1 are implemented in schwannomatosis. But the genotype and phenotype correlation for variants in SMARCB1 has not been determined.Methods: A Chinese schwannomatosis family with an autosomal dominant inheritance pattern was recruited. Whole-exome sequencing (WES) was performed to discover the causative variant, followed by Sanger sequencing. We evaluated the Human Gene Mutation Database (HGMD) regarding SMARCB1 variants and validated associated phenotype records to assess phenotype-genotype relationships. Results: A novel deletion variant c.885_896delGAAGCTGTGCTC p.(295_299del） in SMARCB1 was identified in the affected family members and cosegregated with phenotypes in the pedigree. About 51.1% of variants in SMARCB1 located in Snf5 subunit, 80.7% of variants were loss-of-function (LOF) variants, and more variants located in the Snf5 subunit of SMARCB1 in Rhabdoid tumour (67.8%) than that in schwannomatosis (25.7%).Conclusions: Our study expands the variant spectrum of SMARCB1 and the genetic background of schwannomatosis, confirms the clinical indications for genetic screening of the SMARCB1 gene, and has implications for genetic counseling in this disease.

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Identification of a novel variant in GPR56/ADGRG1 gene through whole exome sequencing in a consanguineous Pakistani family

Journal of Clinical Neuroscience ◽

10.1016/j.jocn.2021.09.027 ◽

2021 ◽

Vol 94 ◽

pp. 8-12

Author(s):

Shumaila Zulfiqar ◽

Muhammad Tariq ◽

Shafaq Ramzan ◽

Ayaz Khan ◽

Muhammad Sher ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pakistani Family ◽

Whole Exome ◽

Novel Variant

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A maternal GOT1 novel variant associated with early-onset severe preeclampsia identified by whole-exome sequencing

BMC Medical Genetics ◽

10.1186/s12881-020-0989-2 ◽

2020 ◽

Vol 21 (1) ◽

Cited By ~ 1

Author(s):

Lin Zhang ◽

Zheng Cao ◽

Fan Feng ◽

Ya-Nan Xu ◽

Lin Li ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Severe Preeclampsia ◽

Whole Exome ◽

Novel Variant

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Whole Exome Sequencing in Early-onset Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.171358 ◽

2018 ◽

Vol 45 (12) ◽

pp. 1671-1679 ◽

Cited By ~ 5

Author(s):

Ezgi Deniz Batu ◽

Can Koşukcu ◽

Ekim Taşkıran ◽

Sezgin Sahin ◽

Sema Akman ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Lupus Erythematosus ◽

Early Onset ◽

Sanger Sequencing ◽

Systemic Lupus ◽

Whole Exome ◽

Novel Variant ◽

Missense Alteration

Objective.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Early-onset, familial, and/or syndromic SLE may reveal monogenic pathologies. The aim of this study was to examine genetic associations in patients with early-onset or familial SLE.Methods.We enrolled 7 SLE cases (from different families) with disease onset ≤ 5 years of age and family history consistent with an autosomal recessive inheritance. Whole exome sequencing (WES) was performed in 6 index cases. Suspected variants were confirmed by Sanger sequencing. We did not perform WES in 1 patient who had features similar to the first 3 cases; only the exons of C1QA, C1QB, and C1QC were screened with Sanger sequencing.Results.We demonstrated 2 novel and 3 previously reported variants in genes associated with SLE: a homozygous non-sense alteration (c.622C>T/p.Gln208Ter) in C1QA in 2 patients; homozygous non-sense alteration (c.79C>T/p.Gln27Ter) in C1QC in 1 (novel variant); homozygous missense alteration (c.100G>A/p.Gly34Arg) in C1QC in 1; homozygous missense alteration (c.1945G>C/p.Ala649Pro) in C1S in 1 (novel variant); and homozygous frameshift alteration (c.289_290delAC/p.Thr97Ilefs*2) in DNASE1L3 in 1 patient. Further, in 1 patient, we determined a strong candidate variant in HDAC7 (histone decetylase 7).Conclusion.Five patients had homozygous alterations in genes coding early complement proteins. This may lead to decreased clearance of apoptotic bodies. One patient had DNASE1L3 variant, which functions in the clearance of self-antigens. In 1 patient, we determined a novel gene that may be important in SLE pathogenesis. We suggest that monogenic causes/associations should be sought in early-onset and/or familial SLE.

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