New syndromes ,
Mutations in GDF11, and the extracellular antagonist, follistatin, may cause Mendelian forms of orofacial clefting in humans
A new article published in Human Mutation reported the identification, via exome sequencing, of likely pathogenic variants in two genes that encode interacting proteins previously only linked to orofacial clefting in mouse models. A variant in GDF11 (encoding growth differentiation factor 11) was identified in one family that segregated with cleft lip with or without cleft palat and both rib and vertebral hypersegmentation, mirroring that seen in Gdf11 knockout mice. In the second family in which cleft lip with or without cleft palat was the only phenotype, a mutation in FST (encoding the GDF11 antagonist, Follistatin) was identified that is predicted to result in a substitution in the region that binds GDF1. This study provided strong evidence for the importance of GDF11 and Follistatin in the regulation of human orofacial development.
- Hum Mutat. 2019 Oct;40(10):1813-1825
ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular and multisystem autosomal dominant disorder
A new study recently published in Genetics in Medicine identified five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. The heterozygous missense variant in the ɑ-kinase gene, ALPK1, segregated with disease in all five families was identified. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. Heterozygosity for ALPK1 leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder. Heterozygosity for ALPK1 leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
- Genet Med. 2019 Sep;21(9):2103-2115
Recessive mutations in the homeobox gene GSX2 cause agenesis of the putamen and globus pallidus
A new study published in Brain identified two unrelated children presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development.This sutdy was the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans.
- Brain. 2019 Oct 1;142(10):2965-2978
Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination
A study published in Brain identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene. This study highlighter the importance of this gene in human brain development and function.
- Brain. 2019 Oct 1;142(10):2948-2964
De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye, and digit anomalies
A new study recently published in The American Journal of Human Genetics identified seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. This study supported the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.
- Am J Hum Genet. 2019 Sep 5;105(3):640-657
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