Novel de novo SPOCK1 mutation in a proband with developmental delay,microcephaly and agenesis of corpus callosum

Whole exome sequencing made it possible to identify novel de novo mutations in genes that might be linked to human syndromes (genotype first analysis). We describe a female patient with a novel de novo SPOCK1 variant, which has not been previously been associated with a human phenotype. Her features include intellectual disability with dyspraxia, dysarthria, partial agenesis of corpus callosum, prenatal-onset microcephaly and atrial septal defect with aberrant subclavian artery. Previous genetic, cytogenomic and metabolic studies were unrevealing. At age 13 years, exome sequencing on the patient and her parents revealed a de novo novel missense mutation in SPOCK1 (coding for Testican-1) on chromosome 5q31: c.239A>T (p.D80V). This mutation affects a highly evolutionarily conserved area of the gene, replacing a polar aspartic acid with hydrophobic nonpolar valine, and changing the chemical properties of the protein product, likely representing a pathogenic variant. Previous microdeletions of 5q31 including SPOCK1 have suggested genes on 5q31 as candidates for intellectual disability. No mutations or variants in other genes potentially linked to her phenotype were identified. Testicans are proteoglycans belonging to the BM-40/SPARC/osteonectin family of extracellular calcium-binding proteins. Testican-1 is encoded by the SPOCK1 gene, and mouse models have been shown it to be strongly expressed in the brain and to be involved in neurogenesis. We hypothesize that because this gene function is critical for neurogenesis, mutations could potentially lead to a phenotype with developmental delay and microcephaly.     

Polyasplenia, caudal deficiency, and agenesis of the corpus callosum

Fullana et al. [Am J Med Genet (suppl. 2): 23-29, 1986] reported on 2 sibs with an autosomal recessive syndrome of caudal deficiency and polyasplenia anomalies. We report on a similar patient in which agenesis of the corpus callosum (ACC) was also found. Such an association has not been reported previously. This finding of ACC is to be interpreted as another midline anomaly rather than as a causally independent malformation.     

Humero-radial synostosis, microcephaly, short corpus callosum, and abnormal genitalia in sibs

We report on two male sib fetuses with humero-radial synostosis and thumb hypoplasia, microcephaly with simplified gyral pattern, short corpus callosum and ambiguous genitalia. The main clinical, anatomopathological and imaging findings are presented and compared with previous cases of humero-radial synostosis as a prominent manifestation and with the X-linked lissencephaly with ambiguous genitalia syndrome (X-LAG). To our knowledge, this combination of anomalies has never been described before, and we propose that this disorder comprises a new humero-radial synostosis syndrome with an autosomal recessive or X-linked pattern of inheritance.     

De novo microdeletion of 5q14.3 excluding MEF2C in a patient with infantile spasms, microcephaly, and agenesis of the corpus callosum

The 5q14.3 microdeletion syndrome has recently been recognized as a clinical entity manifesting as severe intellectual disability, epilepsy, and brain malformations. Analysis of the shortest region of overlap among patients with this syndrome and subsequent identification of nucleotide alterations in the coding region of myocyte enhancer factor 2C gene (MEF2C) have suggested MEF2C as the gene responsible for the 5q14.3 microdeletion syndrome. We identified a de novo 3.4-Mb deletion of 5q14.3 in a patient with infantile spasms, microcephaly, and brain malformation. The deleted region in the present patient was positional toward the centromere, and MEF2C was not included in the deleted region. However the neurological and dysmorphic features of the present patient resembled those of patients with the 5q14.3 microdeletion syndrome. We consider that a positional effect is the likely explanation for this evidence. To study the precise mechanism of this positional effect, further information is required on patients showing atypical deletions neighboring MEF2C. ? 2012 Wiley Periodicals, Inc.     

Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum,pontine hypoplasia,focal white matter changes,hypotonia, mental retardation,and minor anomalies

We describe a brother and sister with severe developmental delay, hypotonia, partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter degenerative abnormalities, macrocrania, frontal bossing, deep-set eyes, and hypertelorism. The brother also had Duane syndrome type II and an ectopic right ureter. The coexistence of these multiple physical and brain abnormalities in a brother and sister suggests a new autosomal recessive syndrome with a slowly progressive course. Am. J. Med. Genet. 73:184–188, 1997. © 1997 Wiley-Liss, Inc.     

Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections

A sister and brother with Vici syndrome are described. They both had oculocutaneous albinism, agenesis of the corpus callosum, cataracts, and cardiomyopathy. They were born to healthy unrelated parents, and had postnatal growth retardation, profound developmental delay, hypotonia, and cataracts. The sister had recurrent infections, and died of progressive heart failure at age 19 months. The brother is alive at age six months with mild cardiomyopathy, and had a single episode of acute bronchitis at age three months. Review of the clinical manifestations of the sibs we described and six children reported in the literature indicates that Vici syndrome is a distinct clinical entity. Its main clinical manifestations include growth retardation, profound developmental delay, hypotonia, albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, and recurrent infections. The occurrence of the syndrome in three pairs of sibs of both sexes born to unaffected parents supports autosomal recessive inheritance.     

A new X-linked syndrome with agenesis of the corpus callosum, mental retardation, coloboma, micrognathia, and a mutation in the Alpha 4 gene at Xq13

We describe two brothers with a unique pattern of malformations that includes coloboma (iris, optic nerve), high forehead, severe retrognathia, mental retardation, and agenesis of the corpus callosum (ACC). Both boys have low-set cupped ears with sensorineural hearing loss, normal phallus, pectus excavatum, scoliosis, and short stature. One brother had choanal atresia and cardiac defects consisting of ventricular septal defect (VSD) and patent ductus arteriosus (PDA) which resolved spontaneously. Differential diagnosis between a number of clinical entities was considered, however, because ACC and the distinctive facial features were reminiscent of FG syndrome, DNA was analyzed for markers linked to the FGS1 locus at Xq13-q21. Notably, the brothers were concordant for markers spanning this presumed FG region, and in both we have identified adjacent alterations (-57delT and T-55A) in the Alpha 4 gene located within this interval. Alpha 4 is a regulatory subunit of the major cellular phosphatase, PP2A, that has recently been shown to interact with MID1, the product of the gene mutated in X-linked Opitz GBBB syndrome. The double nucleotide change identified in this family was not observed in 410 control chromosomes, suggesting that it may be a pathogenetic change. Altered expression of Alpha 4, through either a change in translational efficiency, mRNA stability or splicing, could explain the clinical phenotype in these boys and the phenotypic overlap with Opitz GBBB syndrome.     

New X-linked syndrome with seizures, acquired micrencephaly, and agenesis of the corpus callosum.

We report on 4 generations in a family with 3 living males, 3 males who died in infancy, and 3 females with neurologic impairment and agenesis of the corpus callosum (ACC). Manifestations in the surviving males include severe acquired micrencephaly, mental retardation, limb contractures, scoliosis, tapered digits with hyperconvex nails, a characteristic face with large eyes, prominent supraorbital ridges, synophris, optic atrophy, broad alveolar ridges and seizures. Urologic anomalies include renal dysplasia, cryptorchidism, and hypospadias. Two affected females were less severely impaired and continued to be socially responsive as adults, but had spastic quadriplegia and seizures. One obligate heterozygote was retarded with emotional problems while another obligate carrier female and her daughter were clinically normal. Pedigree analysis suggested X-linked inheritance with variable expression in females. These findings are inconsistent with the well-described X-linked conditions with ACC including FG syndrome and Aicairdi syndrome. ACC has not been described in Coffin-Lowry syndrome, a condition with similar clinical findings, which also demonstrates marked variability of expression in carrier females. In order to assist in carrier determination, brain imaging studies and DNA linkage analysis of the affected relatives was performed. We found a spectrum of agenesis of the corpus callosum with the most severe manifestations in the most severely affected males. DNA analysis using a series of X-linked probes suggests linkage with a LOD score of 1.26 at theta = 0 to a region between p 11.3 and p 21.3.     

Hypohidrotic ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum.

In this report we present the unique combination of hypohidrotic ectodermal dysplasia, primary hypothyroidism, and agenesis of the corpus callosum in a two year old, severely mentally retarded boy.     

Partial agenesis of the corpus callosum, hippocampal atrophy, and stable intellectual disability associated with Roifman syndrome

In 2006, we reported the cognitive and behavioral phenotype of the seventh case of Roifman syndrome (OMIM 300258). Aged 11 years 6 months, the patient displayed significant intellectual disability with proportionate impairments in attentional-executive, memory, and visuo-spatial abilities despite appearing socially "able." This discrepancy may be explained by good social-emotional skills masking his intellectual disability, by decline in cognitive abilities over time, or by unusual neuroradiological abnormalities not previously examined in Roifman syndrome. Here, we present results from a structural MRI scan, neurocognitive evaluations repeated 2 and 5 years post-baseline and assessments of face and emotional processing. The MRI revealed partial agenesis of the corpus callosum, bilateral hypoplastic hippocampi but bilaterally intact amygdala. No evidence was found for decline in the patient's neurocognitive profile. Emotional processing data indicated an age-appropriate pattern of reactivity to emotional stimuli and preserved facial identity recognition abilities, but impairments in recognition of negative facial expressions. The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities. We suggest that the relative strengths in emotion and face processing are consistent with the patient's apparently able social behavior, and with intact amygdalar function.     

A 6.9 Mb 1qter deletion/4.4 Mb 18pter duplication in a boy with extreme microcephaly with simplified gyral pattern, vermis hypoplasia and corpus callosum agenesis

We here report a boy presenting with developmental delay, growth retardation, facial dysmorphisms, vermis hypoplasia, micropolygyria and corpus callosum agenesis. Conventional and high resolution cytogenetic analyses were normal but high resolution oligonucleotide array-CGH, performed at the age of 4 years, allowed the characterisation of a de novo 6.9 Mb 1qter deletion/4.4 Mb 18pter duplication. Numerous 1qter deletions have already been described associated with brain malformations. Among 1q44 deleted genes, AKT3 is the strongest candidate gene for vermis hypoplasia and corpus callosum agenesis.     

Sleep architecture in agenesis of the corpus callosum: laboratory assessment of four cases

SUMMARY  Whether the corpus callosum is essential for normal human sleep cannot be decided from current knowledge. We thus studied sleep architecture in four subjects with agenesis of the corpus callosum (ACC) and four control subjects matched for age, gender, and hand preference. All-night EEG, EOG, and EMG activity were monitored in the laboratory for one adaptation night and one data acquisition night. Standard sleep variables were calculated for the second night.
Agenesis subjects were found to have a greater percentage of stage 3 + 4 sleep and a lower percentage of stage 2 sleep than control subjects. Agenesis subjects also tended to have more REM sleep periods and a shorter REM cycle length than controls.
The pattern of results is similar to that produced by partial callosotomy. It is also relevant to two hypotheses about the function of the corpus callosum in sleep. First, the corpus callosum may facilitate synchronization of activity between homologous regions in the two hemispheres but interfere with synchronization of neuronal populations within each hemisphere. Its absence may thus explain both an augmentation of slow-wave activity (and thus more slow-wave sleep) and a decrease in interhemispheric EEG coherence. Secondly, the corpus callosum may play a role in the regulation of the ultradian rhythm which underlies timing and duration of REM sleep.     

Orofaciodigital syndrome type I associated with polycystic kidneys and agenesis of the corpus callosum.

We report a female case of orofaciodigital syndrome type I (OFD I) associated with polycystic kidneys and agenesis of the corpus callosum. She had chronic renal failure requiring maintenance dialysis and significant neurological deficits. Her mother had less severe OFD I associated with polycystic kidneys but her renal function was normal and there was no clinical or radiological evidence of a structural abnormality of the brain.     

Dreaming in agenesis of the corpus callosum: laboratory and home assessment of four cases

Laboratory and home dream recall was studied in four subjects with agenesis of the corpus callosum and in four control subjects who were matched for age, gender, and handedness. In addition, the structural and emotional content of home dreams was compared for these two groups. Results indicate that acallosal subjects recalled fewer dreams in the laboratory than did control subjects, but recalled the same number of dreams at home. They also reported more contentless dreams in both situations. Furthermore, although acallosal subjects used fewer words to describe their dream content in both contexts, the number of content categories they reported differed little from the number reported by control subjects. However, some trends were found for acallosal's home dreams to differ from those of controls, i.e. more dreams with known characters and fewer dreams with unknown characters, animals, and colours. Differences in emotional contents were few; acallosals reported more distress than controls. The shorter length of acallosals' dreams might be explained, in part, by their lower verbal IQs. Other characteristics of dream content (e.g. more distress, fewer dreams with unknown and animal characters) may reflect limited social experiences in this group. However, the greater frequency of contentless dreams and the lower frequency of dreams with colour are trends consistent with the possibility that the corpus callosum may be implicated in processes of dream production and dream recall.