SPTBN4 – Neurodevelopmental Disorder with Hypotonia, Neuropathy, and Deafness

SPTBN4 is associated with Neurodevelopmental Disorder with Hypotonia, Neuropathy, and Deafness, an autosomal recessive syndrome characterized by severe muscular hypotonia, motor and auditory neuropathy, deafness, and global developmental delay.

Five probands across four unrelated families have been described with homozygous or compound heterozygous SPTBN4 variants, including a multi-exon deletion [PMID:33772159]. Two siblings with a homozygous splice‐site variant were reported in a separate cohort [PMID:31857255]. Five additional probands in three families harboring bi-allelic missense, nonsense, and frameshift variants have been documented [PMID:29861105]. These twelve probands in eight families, with segregation in affected siblings and concordant functional studies, support a Strong ClinGen gene–disease association.

Inheritance is autosomal recessive, with segregation confirmed in one sib-pair [PMID:31857255]. The variant spectrum includes missense (e.g., c.1511G>A (p.Arg504Gln)), nonsense (c.3820G>T (p.Glu1274Ter)), frameshift (c.7453del (p.Ala2485fs)), splice (c.3949-1G>A), and multi-exon deletion alleles. No recurrent or founder alleles have been reported; prevalence and carrier frequency remain undefined. Compound heterozygous and homozygous genotypes correlate with severity of hypotonia and neuropathy.

Functional analyses demonstrate loss-of-function as the pathogenic mechanism. In vitro expression of five of seven SPTBN4 variants disrupted ankyrinG clustering and ion channel localization at the axon initial segment, abolishing phosphoinositide binding [PMID:29861105]. A murine knock-in model recapitulated motor axonal neuropathy and nodal channel deficits. Histochemical studies of patient muscle biopsies reveal combined myopathic and neuropathic changes concordant with human phenotype [PMID:33772159].

No studies to date have refuted the association or described dominant-negative effects. Alternative phenotypes without intellectual disability have been noted in pure neuropathy cases but remain within the recessive spectrum [PMID:31857255].

Together, genetic and functional data coherently establish that bi-allelic loss-of-function SPTBN4 variants cause Neurodevelopmental Disorder with Hypotonia, Neuropathy, and Deafness. This evidence meets Strong ClinGen criteria for clinical validity. Key Take-home: SPTBN4 sequencing should be included in diagnostic panels for early-onset hypotonia with neuropathy and deafness.

References

• European journal of human genetics • 2021 • Novel bi-allelic variants expand the SPTBN4-related genetic and phenotypic spectrum. PMID:33772159
• European journal of medical genetics • 2020 • A novel homozygous splice-site mutation in the SPTBN4 gene causes axonal neuropathy without intellectual disability. PMID:31857255
• American journal of human genetics • 2018 • βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy PMID:29861105

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