Mol Genet Genomic Med. 2021 Jun 2:e1623. doi: 10.1002/mgg3.1623. Online ahead of print. ABSTRACT BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS. METHODS: A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS). RESULTS: WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation. CONCLUSION: The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing. PMID:34076366 | DOI:10.1002/mgg3.1623

BMC Neurol. 2020 Jun 16;20(1):246. doi: 10.1186/s12883-020-01798-x. ABSTRACT BACKGROUND: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene. CASE PRESENTATION: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. CONCLUSION: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members. PMID:32546208 | PMC:PMC7296679 | DOI:10.1186/s12883-020-01798-x

Genome Med. 2020 May 27;12(1):48. doi: 10.1186/s13073-020-00748-z. ABSTRACT Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practice. The Medical Genome Initiative consortium was formed to provide practical guidance and support the development of standards for the use of clinical WGS. PMID:32460895 | PMC:PMC7254704 | DOI:10.1186/s13073-020-00748-z

Orphanet J Rare Dis. 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8. ABSTRACT BACKGROUND: Tetrahydrobiopterin (BH₄) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH₄ biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH₄ deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH₄ deficiencies. CONCLUSION: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH₄ deficient patients. PMID:32456656 | PMC:PMC7251883 | DOI:10.1186/s13023-020-01379-8

J Inherit Metab Dis. 2020 Sep;43(5):1024-1036. doi: 10.1002/jimd.12232. Epub 2020 Apr 15. ABSTRACT Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease. PMID:32160317 | PMC:PMC7484123 | DOI:10.1002/jimd.12232

Hum Genet. 2020 May;139(5):569-574. doi: 10.1007/s00439-020-02135-5. Epub 2020 Feb 13. ABSTRACT Extremely rare diseases are increasingly recognized due to wide-spread, inexpensive genomic sequencing. Understanding the incidence of rare disease is important for appreciating its health impact and allocating recourses for research. However, estimating incidence of rare disease is challenging because the individual contributory alleles are, themselves, extremely rare. We propose a new method to determine incidence of rare, severe, recessive disease in non-consanguineous populations that use known allele frequencies, estimate the combined allele frequency of observed alleles and estimate the number of causative alleles that are thus far unobserved in a disease cohort. Experiments on simulated and real data show that this approach is a feasible method to estimate the incidence of rare disease in European populations but due to several limitations in our ability to assess the full spectrum of pathogenic mutations serves as a useful tool to provide a lower threshold on disease incidence. PMID:32056000 | PMC:PMC7176520 | DOI:10.1007/s00439-020-02135-5

Sci Transl Med. 2019 Apr 24;11(489):eaat6177. doi: 10.1126/scitranslmed.aat6177. ABSTRACT By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children’s deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient’s CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient’s genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments. PMID:31019026 | DOI:10.1126/scitranslmed.aat6177