SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss

PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with >99% analytical sensitivity and specificity for single-nucleotide variants and indels <10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings.

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“…Pathogenic variants in SPATA5 have since been recognized to be associated with seizures and intellectual disability. 28,29…”

Section: Case 16mentioning

confidence: 99%

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Gibson

Nesbitt

Cao

et al. 2018

Genetics in Medicine

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“…one heterozygous carrier) in the Exome Aggregation Consortium (ExAC) database [ 10 ]. The c.989_991del in-frame deletion has been previously reported in multiple patients with SPATA5- related disorder [ 1 – 3 ]. Both variants were confirmed by Sanger sequencing in both, Patients 1 and 2.…”

Section: Resultsmentioning

confidence: 99%

“…Autosomal recessive variants in the SPATA5 (spermatogenesis-associated protein 5, MIM: 613940) gene were recently associated with a specific disease phenotype. Tanaka et al [ 1 ], Kurata et al [ 2 ] and Buchert et al [ 3 ] reported 25 individuals with intellectual disability, microcephaly, hypotonia, spasticity, seizures, sensorineural hearing loss and cortical visual impairment.…”

Section: Introductionmentioning

confidence: 99%

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Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency

et al. 2018

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Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene. A summary of clinical data of all the SPATA5 patients reported in the literature confirms the characteristic phenotype. To assess SPATA5’s role in mitochondrial dynamics, functional studies were performed on rat cortical neurons. SPATA5-deficient neurons had a significant imbalance in the mitochondrial fusion-fission rate, impaired energy production and short axons. In conclusion, SPATA5 protein has an important role in mitochondrial dynamics and axonal growth. Biallelic variants in the SPATA5 gene can affect mitochondria in cortical neurons and should be considered in patients with a neurodegenerative disorder and/or with clinical presentation resembling a mitochondrial disorder.

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“…But the following studies of SPATA5 have suggested a role of the SPATA5 gene not only in neuronal development but also in spermatogenesis. It was dominantly cytosolic in cortical neurons [33][34][35][36]. The SPATA5 deficiency affects mitochondrial morphology and inhibits mitochondrial dynamics, delays neuronal development, and is also associated with decreased cellular ATP [36].…”

Section: Discussionmentioning

confidence: 99%

4q27 deletion and 7q36.1 microduplication in a patient with multiple malformations and hearing loss: a case report

Zheng

Wang

et al. 2020

BMC Med Genomics

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Background: Chromosome deletions of the long arm of chromosome 4 in 4q syndrome are characterized by mild facial and digital dysmorphism, developmental delay, growth retardation, and skeletal and cardiac anomalies, which is regarded as an autism spectrum disorder. Moreover, some scarce reports indicate that patients with 4q interstitial deletion and 7p duplication may present symptoms associated with hearing loss. Case presentation: A boy with a severe developmental delay not only post-natal but also intrauterine and several dysmorphic features including microcephaly, ocular hypertelorism, exophthalmos, low-set ears, single palmar flexion crease, and overlapping toes presented discontinued cyanosis and recurrent respiratory infections. MRI, BAEP, echocardiogram and bronchoscopy revealed that he had persistent falcine sinus with a thin corpus callosum, left auditory pathway disorder, patent foramen ovale (2 mm), and tracheobronchomalacia with the right superior bronchus arising from the lateral posterior wall of the right main bronchus. Finally, the patient died with severe pneumonia at 10 months. Array CGH revealed a 23.62 Mb deletion at chromosome 4q27, arr [hg19] 4q27-q31.21 (121, 148, 089-144, 769, 263) × 1, and a 0.85 Mb duplication at chromosome 7q36.1, arr [hg19] 7q36.1-q36.2 (152, 510, 685-153, 363,5 98) × 3. It is rare for 4q syndrome cases or 7q duplications previously reported to have a hearing disorder, pulmonary dysplasia, and pulmonary arterial hypertension. Conclusions: The phenotype of our patient mainly reflects the effects of haploinsufficiency of FGF2, SPATA5, NAA15, SMAD1, HHIP genes combined with a microduplication of 7q36.1.

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SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss

Cited by 23 publications

References 26 publications

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data

Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency

4q27 deletion and 7q36.1 microduplication in a patient with multiple malformations and hearing loss: a case report

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