Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and consequently which of the three major SOX5 protein isoforms are affected. One intragenic deletion involving only untranslated exons was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

Simpson-Golabi Behmel syndrome (SGBS) is an X-linked disorder characterized by pre- and postnatal macrosomia, minor facial anomalies, and variable visceral, skeletal, and neurological abnormalities. Since its first description by Simpson et al. [1975: BD:OA XI(2):18-24], a wide clinical range of cases has been reported. There is great variability in severity, ranging from a mild form associated with long-term survival to an early lethal form with multiple congenital anomalies and severe mental retardation. In 8 reported families, affected individuals died in infancy. Here we present 4 maternally related, male cousins with a severe variant of SGBS. One of these males was aborted therapeutically at 19 weeks of gestation following the detection of multicystic kidneys on ultrasound. The 3 liveborn males were hydropic at birth with a combination of craniofacial anomalies including macrocephaly; apparently low-set, posteriorly angulated ears; hypertelorism; short, broad nose with anteverted nares; large mouth with thin upper vermilion border; prominent philtrum; high-arched or cleft palate; short neck; redundant skin; hypoplastic nails; skeletal defects involving upper and lower limbs; gastrointestinal and genitourinary anomalies. All 3 patients were hypotonic and neurologically impaired from birth. With the exception of a trilobate left lung in one patient, the cardiorespiratory system was structurally normal. All patients died within the first 8 weeks of life of multiple complications including pneumonia and sepsis. Two SGBS kindreds, with moderate expression of the condition, have been mapped to Xq27. It is not known whether severe, familial cases, such as ours, are genetically distinct from and map to another locus. Final resolution of the genetic basis of the phenotypic variability in SGBS must await cloning and mutation analysis of the SGBS gene(s).