SPATA5 mutations cause a distinct autosomal recessive phenotype of intellectual disability, hypotonia and hearing loss.
We examined an extended, consanguineous family with seven individuals with severe intellectual disability and microcephaly. Further symptoms were hearing loss, vision impairment, gastrointestinal disturbances, and slow and asymmetric waves in the EEG. Linkage analysis followed by exome sequencing revealed a homozygous variant in SPATA5 (c.1822_1824del; p.Asp608del), which segregates with the phenotype in the family. Molecular modelling suggested a deleterious effect of the identified alterations on the protein function. In an unrelated family, we identified compound heterozygous variants in SPATA5 (c.[2081G > A];[989_991delCAA]; p.[Gly694Glu];[.Thr330del]) in a further individual with global developmental delay, infantile spasms, profound dystonia, and sensorineural hearing loss. Molecular modelling suggested an impairment of protein function in the presence of both variants.SPATA5 is a member of the ATPase associated with diverse activities (AAA) protein family and was very recently reported in one publication to be mutated in individuals with intellectual disability, epilepsy and hearing loss. Our results describe new, probably pathogenic variants in SPATA5 that were identified in individuals with a comparable phenotype. We thus independently confirm that bi-allelic pathogenic variants in SPATA5 cause a syndromic form of intellectual disability, and we delineate its clinical presentation.
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.|Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076, Tübingen, Germany.
Rebecca
R
Buchert
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Addie I
AI
Nesbitt
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.
Hasan
H
Tawamie
Division of Human Genetics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Ian D
ID
Krantz
Division of Child Neurology, Departments of Pediatrics and Neurology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Livija
L
Medne
Division of Neurology, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA, 19104-4399, USA.|Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel Campus, Kiel, Germany.
Ingo
I
Helbig
Division of Human Genetics, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Dena R
DR
Matalon
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.
André
A
Reis
Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.|Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Avni
A
Santani
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany.
Heinrich
H
Sticht
Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, 91054, Erlangen, Germany. Rami.AbouJamra@medizin.uni-leipzig.de.|Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103, Leipzig, Germany. Rami.AbouJamra@medizin.uni-leipzig.de.
Rami
R
Abou Jamra
ARID; Hearing loss; Hypotonia; Microcephaly; NGS
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