De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

COMT and anxiety and cognition in children with chromosome 22q11.2 deletion syndrome.

The COMT gene is thought to contribute to the cognitive/psychiatric phenotypes in 22q11.2 deletion syndrome. We measured these manifestations against the Val/Met alleles of the COMT gene, in 40 nonpsychotic 22q11DS children. The Val allele was associated with poor IQ, processing speed, executive function and a higher frequency of anxiety disorders, underscoring the importance of the COMT gene in the childhood psychopathology in 22q11DS.

Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.

Abnormalities of the corpus callosum in nonpsychotic children with chromosome 22q11 deletion syndrome.

Chromosome 22q11 deletion syndrome (22q11DS) is associated with elevated rates of schizophrenia and other psychoses in adulthood. Childhood morphologic brain abnormalities are frequently reported, but the significance of these and their relationship to the development of schizophrenia are unclear. We sought to delineate midline neuroanatomical abnormalities in nonpsychotic children with 22q11DS and their age- and sex-matched controls and compare these to those reported in individuals with schizophrenia. On qualitative analysis, we found a high incidence of midline developmental abnormalities (cavum septum pellucidum, or CSP). On quantitative analysis, the total corpus callosum (CC) area was significantly increased in the patient group and among the subregions, the patients had a significantly larger isthmus. These findings of an increased area of the corpus callosum, specifically the isthmus, have not been reported before in individuals with 22q11DS. We also found a relative lack of the age-related increase in the size of the corpus callosum in the children with 22q11DS. There were no differences in cerebellar vermis measurements between the patient and control groups. Our findings are indicative of frequent midline brain anomalies, including dysgenesis of the corpus callosum, in nonpsychotic children with 22q11DS. Although the increased size of the corpus callosum in our 22q11DS patients is in direct contrast to the decrease seen in schizophrenia, the high frequency of structural midline abnormalities in these nonpsychotic children with 22q11DS is similar to that seen in schizophrenia. Further longitudinal studies on these children will help determine which of these structural abnormalities is/are pertinent to the development of psychosis.

Vasomotor instability in neonates with chromosome 22q11 deletion syndrome.

Approximately 70% of individuals with chromosome 22q11 deletion syndrome (22q11DS) have congenital heart defects. A host of other vascular problems in these patients, such as tortuous carotid arteries, Raynaud's phenomenon, unexplained hypotension, hypertension, and hypothermia, raise the possibility that there may be abnormal autonomic regulation of the vascular system. So far, however, there has been no formal report of autonomic dysfunction in patients with 22q11 deletion. We present two infants with 22q11DS, who had profound hypotension after uncomplicated surgeries for congenital heart disease. The hypotension was not responsive to vasopressor treatment (and extracorporeal membrane oxygenation in one infant) and resulted in death, due to multiorgan system failure. Obvious causes, such as poor cardiac contractility, prolonged circulatory arrest, neurological abnormality, sepsis and blood loss were excluded. On autopsy, no abnormalities were found that could explain the hypotension. We hypothesize that these infants died of severe hypotension due to abnormal vascular tone and that this is a variable feature in individuals with 22q11 deletion. The autonomic nervous system, which is responsible for the regulation of vasomotor tone, may be variably affected in 22q11DS. This could have implications for the surgical management of patients with 22q11DS. Further studies on this topic would establish or refute the association between 22q11DS and dysautonomia.

A combination of physical examination and ECG detects the majority of hemodynamically significant heart defects in neonates with Down syndrome.

Echocardiography has become the method of choice in the diagnosis of a congenital heart defect (CHD) in neonates with Down syndrome. The most compelling argument for diagnosis of CHD in the neonatal period is the need for early surgical intervention (ideally prior to 6 months of age) in those with a complete atrioventricular (AV) canal. We evaluated the efficacy of a combined approach of physical examination (PE) and electrocardiography (ECG) in the detection of CHD in 49 neonates with Down syndrome. Our findings indicate that most hemodynamically significant defects (78%), especially a complete AV canal, can be detected by this approach. Hemodynamically insignificant minor defects, such as a small patent ductus arteriosus (PDA) and a small atrial septal defect (ASD), may be missed. Thus, echocardiography remains the most sensitive way to diagnose CHD. However, given that the combination of PE and ECG detects the majority of complete AV canal defects, it can be used as an alternative approach when echocardiography is not easily accessible, due to geographic or economic constraints. Follow-up after a few weeks of those with normal PE and ECG findings should enable detection of new symptoms and signs and evolving ECG findings that may have been missed in the immediate newborn period. Patients who are judged by PE and ECG to have CHD will need echocardiographic confirmation.