Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease.

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

A family with cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency presenting with aplastic anaemia.

Acquired aplastic anaemia is a rare disease, and occurrence in more than one member of the same family is uncommon. With this case report, we wish to highlight the importance of searching for an underlying genetic cause when this occurs. It may have consequences for future generations in affected families. CTLA4 haploinsufficiency is a heterogeneous disease entity with severe systemic immune dysregulation associated with several autoimmune diseases including aplastic anaemia.

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype. METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations. RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism. CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report.

BACKGROUND: Persistent pulmonary hypertension is a well-known disease of the newborn that in most cases responds well to treatment with nitric oxide and treatment of any underlying causes. Genetic causes of persistent pulmonary hypertension of the newborn are rare. The TWIST1 gene is involved in morphogenetics, and deletions are known to cause Saethre-Chotzen syndrome. Deletions of PHF14 have never been reported in neonates, but animal studies have shown a link between severe defects in lung development and deletions of this gene. There have not, to the best of our knowledge, been any publications of a link between the genes TWIST1 and PHF14 and persistent pulmonary hypertension of the newborn, making this a novel finding. CASE PRESENTATION: We describe a white male neonate born at term to non-consanguineous white parents; he presented with dysmorphic features and a therapy-refractory persistent pulmonary hypertension. Array-based comparative genomic hybridization revealed the presence of a 14.7 Mb interstitial deletion on chromosome 7, encompassing the genes TWIST1 and PHF14. CONCLUSIONS: The TWIST1 gene can explain our patient's dysmorphic features. His severe persistent pulmonary hypertension has, however, not been described before in conjunction with the TWIST1 gene, but could be explained by involvement of PHF14, consistent with findings in animal experiments showing lethal respiratory failure with depletion of PHF14. These findings are novel and of importance for the clinical management and diagnostic workup of neonates with severe persistent pulmonary hypertension of the newborn and dysmorphic features.

Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder.

Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.