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Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia‐mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss‐of‐function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13‐year‐old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of SHH: Chr7(GRCh38):g.155802987C > T, NM_000193.4:c.1302G > A, p.(Trp434*). The second patient was a 25‐year‐old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of SHH: Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism‐holoprosencephaly phenotype associated with loss‐of‐function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism. [ABSTRACT FROM AUTHOR]

The article describes the case of a 32-year-old Japanese woman of inborn good health who experienced fever and EBV viremia. Topics discussed include findings on laboratory tests, the hospital admission of the patient at the age of 35 years becuase of dyspnea and pancytopenia, and her death 68 days after admission, despite intensive care.

Mutations in the FBXO28 gene, which encodes FBXO28, one of the F-box protein family, may cause developmental and epileptic encephalopathy (DEE). FBXO28 -related DEE is radiologically characterized by cerebral atrophy, delayed/abnormal myelination, and brain malformation; however, no neurochemical analyses have been reported. Case report: A female Japanese infant presented with severe psychomotor delay, epileptic spasms, and visual impairment. Whole-exome sequencing revealed a de novo variant of the FBXO28 gene, leading to the diagnosis of FBXO28 -related DEE. Magnetic resonance (MR) spectroscopy at 6, 12, and 32 months revealed decreased N -acetylaspartate and choline-containing compounds and increased levels of myoinositol. MR spectroscopy revealed neurochemical derangement in FBXO28 -related DEE, that is, disturbed myelination secondary to neuronal damage with astrogliosis. [ABSTRACT FROM AUTHOR]

When a de novo balanced reciprocal translocation is identified in the patient, the cause of phenotype of the patient can be explained by detecting the breakpoints of the genes. Here, we report a 3‐year‐old patient with developmental delay, autism spectrum disorder, and distinctive facial features who had an apparently balanced translocation between chromosome 3q26 and chromosome 7q36. Nanopore long‐read sequencing revealed that balanced translocation disrupted the KMT2C gene, the haploinsufficiency of which leads to Kleefstra syndrome 2 characterized by delayed psychomotor development, variable intellectual disability and mild dysmorphism. Nanopore long‐read sequencing was shown to be useful in elucidating the exact genetic etiology of patients with nonspecific clinical findings. [ABSTRACT FROM AUTHOR]

Carotid body tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs. [ABSTRACT FROM AUTHOR]

When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an "apparently balanced" de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7‐Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Further analysis using a nanopore long‐read sequencer showed complex rearrangements on both derivative chromosomes 4 and 18 and the deleted chromosome 2. First, the TLL1 locus, which is associated with atrial septal defect, was disrupted by the rearrangement involving chromosome 4. Second, the deleted interval at 2q31 included the entire HOXD cluster, the deletion of which is known to cause toe syndactyly, and the DLX1 and DLX2 loci, which are responsible for cleft lip and palate. Among the haplo‐sensitive genes within the deleted interval on 2q31, only the RAPGEF4 gene is known to be associated with an autistic phenotype. Hence, most of the clinical features of the patient could be ascribed to specific genomic rearrangements. We have shown the effectiveness of long‐read sequencing in defining, in detail, the likely effects of an apparently balanced translocation and cryptic deletion. The results of the present analysis suggest the possibility of phenotypic prediction through a detailed analysis of structural abnormalities, including balanced translocations and deletions. [ABSTRACT FROM AUTHOR]

Menke–Hennekam syndrome‐1 (MKHK1) is a congenital disorder caused by the heterozygous variants in exon 30 or 31 of CREBBP (CREB binding protein) gene mapped on 16p13.3. It is characterized by psychomotor delay, variable impairment of intellectual disability (ID), feeding difficulty, autistic behavior, hearing impairment, short stature, microcephaly, and facial dysmorphisms. The CREBBP loss‐of‐function variants cause Rubinstein–Taybi syndrome‐1 (RSTS1). The function of CREBBP leading to MKHK1 has not been clarified so far, and the phenotype of MKHK1 significantly differs from that of RSTS1. We examined six patients with de novo pathogenic variants affecting the last exon of CREBBP, and they shared the clinical features of MKHK1. This study revealed that one frameshift and three nonsense variants of CREBBP cause MKHK1, and inferred that the nonsense variants of the last exon could further help in the elucidation of the etiology of MKHK1. [ABSTRACT FROM AUTHOR]

• Identical twins with the STXBP1 mutation are extremely rare. • Each patient exhibited different progression of epilepsy and development. • Both patients had Ohtahara syndrome. • While one transitioned to West syndrome, the other showed spontaneous remission. [ABSTRACT FROM AUTHOR]

We previously reported genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of IGF1R, which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants. [ABSTRACT FROM AUTHOR]

Background: Mutations of theADCY5 have been identified in patients with familial dyskinesia, early-onsetautosomal dominant chorea and dystonia, and benign hereditary chorea. Most ofthe ADCY5 mutations are de novo or transmitted in an autosomal dominantfashion. Only two pedigrees are known to show autosomal recessive inheritance. Objectives: We report twosiblings with severe ID, dystonic movement, and growth failure with unknownetiology. Methods: We planned a proband-parentapproach using whole exome sequencing. Results: Homozygous mutationin exon 21 of the ADCY5 (p.R1238W) was identified in the siblings. Althoughtheir parents were heterozygous for the mutation, they were free from clinicalmanifestations. Conclusions: Our results furtherexpand the phenotype/genotype correlations of the ADCY5-related disorders.Mutations of ADCY5 should be considered in pediatric patients with ID andinvoluntary movement. [ABSTRACT FROM AUTHOR]

Objectives: A better understanding of antitumor immunity will help predict the prognosis of gastric cancer patients and tailor the appropriate therapies in each patient. Therefore, we propose a novel immunological classification of gastric cancer. Methods: We performed whole‐exome sequencing (WES), RNA‐Seq and flow cytometry in 29 gastric cancer patients who received surgery. The TCGA data set of 323 gastric cancer patients and RNA‐Seq data of 45 patients who received pembrolizumab (Kim et al. Nat Med 2018; 24: 1449–1458) were also analysed. Results: Immunogram analysis of cancer–immunity interaction of gastric cancer revealed immune signatures of four main types, designated Hot1, Hot2, Intermediate and Cold. Immunologically hot tumors displayed a dysfunctional T‐cell signature, while cold tumors had an exclusion signature. Ex vivo tumor‐infiltrating lymphocyte analysis documented T‐cell dysfunction with the expression of checkpoint molecules and impaired cytokine production. The T‐cell function was more profoundly damaged in Hot1 than Hot2 tumors. Patients in Hot2 subtypes had better survival in our cohort and TCGA cohort. Although these immunological subtypes overlapped to some degree with the molecular subtypes in the TCGA, intratumoral immune responses cannot be predicted solely based on histological or molecular subtyping of gastric cancer. Molecular and immunological classifications complement each other to predict the responses to anti‐PD‐1 therapy and have the potential to be a biomarker for the treatment of gastric cancer. Conclusion: The immunological classification of gastric cancer resulted in four subtypes. Hot tumors were further divided into two subtypes, between which the functional status of T cells was different. [ABSTRACT FROM AUTHOR]

Purpose: To screen for anti‐recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross‐sectionally characterize the seropositive patients clinically. Methods: Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50–80 years, were screened for anti‐recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti‐recoverin antibodies as a control. Results: Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti‐recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti‐recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. Conclusion: Our results show that serum anti‐recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti‐recoverin antibodies. [ABSTRACT FROM AUTHOR]