Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

A Case of HDR Syndrome and Ichthyosis: Dual Diagnosis by Whole-Genome Sequencing of Novel Mutations in GATA3 and STS Genes.

CONTEXT: Atypical presentations of complex multisystem disorders may elude diagnosis based on clinical findings only. Appropriate diagnostic tests may not be available or available tests may not provide appropriate coverage of relevant genomic regions for patients with complex phenotypes. Clinical whole-exome/-genome sequencing is often considered for complex patients lacking a definitive diagnosis. CASE DESCRIPTION: A boy who is now 7 years old presented as a newborn with congenital ichthyosis. At 6 weeks of age, he presented with failure to thrive and hypoparathyroidism. At 4 years of age, he was diagnosed with sensorineural hearing loss. Whole-genome sequencing identified novel mutations in GATA3, which causes HDR syndrome (hypoparathyroidism and deafness), and STS, which causes X -linked congenital ichthyosis. CONCLUSION: Whole-genome sequencing led to a definitive clinical diagnosis in a case where no other clinical test was available for GATA3, and no sequencing panel would have included both genes because they have disparate phenotypes. This case demonstrates the power of whole-genome (or exome) sequencing for patients with complex clinical presentations involving endocrine abnormalities.

Compound heterozygosity of predicted loss-of-function DES variants in a family with recessive desminopathy.

BACKGROUND: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established. CASE PRESENTATION: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent. CONCLUSIONS: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies.

Chromosomal microarray testing influences medical management.

PURPOSE: Chromosomal microarray (CMA) testing provides the highest diagnostic yield for clinical testing of patients with developmental delay (DD), intellectual disability (ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). Despite improved diagnostic yield and studies to support cost-effectiveness, concerns regarding the cost and reimbursement for CMA have been raised because it is perceived that CMA results do not influence medical management. METHODS: We conducted a retrospective chart review of CMA testing performed during a 12-month period on patients with DD/ID, ASD, and congenital anomalies to determine the proportion of cases where abnormal CMA results impacted recommendations for clinical action. RESULTS: Among 1792 patients, 13.1% had clinically relevant results, either abnormal (n = 131; 7.3%) or variants of possible significance (VPS; n = 104; 5.8%). Abnormal variants generated a higher rate of recommendation for clinical action (54%) compared with VPS (34%; Fisher exact test, P = 0.01). CMA results influenced medical care by precipitating medical referrals, diagnostic imaging, or specific laboratory testing. CONCLUSIONS: For all test indications, CMA results influenced medical management in a majority of patients with abnormal variants and a substantial proportion of those with VPS. These results support the use of CMA as a clinical diagnostic test that influences medical management for this patient population.

Duplication of 5q15-q23.2: case report and literature review.

BACKGROUND: Pure partial trisomy of chromosome 5q is rare and cases have ranged over the entire region, making it difficult to describe a good phenotypic correlation to the cytogenetic duplication. CASE: We present a 4.5-year-old girl with a de novo direct duplication of chromosome 5q15-q23.2. She has moderate developmental delay with lack of speech, microcephaly, and subtle dysmorphic features including prominent forehead, bulbous nose, epicanthic folds, protruding tongue, and slightly posteriorly-rotated ears. CONCLUSIONS: A comparison is made with other similar duplication cases reported in the literature and a general description of a proximal 5q duplication phenotype is given, with lack of speech as the principal feature.

Bayesian analysis for cystic fibrosis risks in prenatal and carrier screening.

PURPOSE: Risk assessment is an essential component of genetic counseling and testing, and Bayesian analysis plays a central role in complex risk calculations. We previously developed generalizable Bayesian methods to calculate the autosomal recessive disease risk of a fetus when one or no mutation is detected, and another, independent risk factor is present. Our methods are particularly useful for calculating the CF disease risk for a fetus with echogenic bowel. In genetics practice, however, there are other scenarios for which our previous methods are inadequate. METHODS AND RESULTS: We provide herein methods for calculating genetic risks in a variety of common clinical scenarios. These scenarios include the following: (1) different mutation panels that have been used for the parents and for a fetus; (2) genetic testing results available on the proband or other relatives, in addition to the consultand; (3) fetal ultrasound negative for echogenic bowel with a positive family history; and (4) a consultand with a mixed ethnic background. CONCLUSION: Our Bayesian methods have proven their versatility through application to many different common genetic counseling scenarios. These methods permit autosomal recessive disease and carrier probabilities to be calculated accurately, taking into account all relevant information. Our methods allow accurate genetic risk estimates for patients and their family members for CF or other autosomal recessive disorders.