KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup)

Heterozygous pathogenic variants in the KAT6B gene, which encodes lysine acetyltransferase 6B, have been identified in patients with congenital rare disorders, including genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome. Herein, we report another Japanese patient with a KAT6B-related disorder and a novel de novo heterozygous variant in exon 18 of KAT6B [c.3925dup, p.(Glu1309fs*33)], providing further evidence that truncating variants in exon 17 and in the proximal region of exon 18 are associated with genitopatellar syndrome-like phenotypes

Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in the newborn screening

Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in the SLC25A13 gene. Intrahepatic cholestasis and various metabolic abnormalities, including hypoglycemia, galactosemia, citrullinemia, and hyperammonemia may be present in neonates or infants in the “neonatal intrahepatic cholestasis caused by citrin deficiency” (NICCD) form of the disease. Because at present, newborn screening (NBS) for citrin deficiency using citrulline levels in dried blood spots (DBS) can only detect some of the patients, we tried to develop a new evaluation system to more reliably detect newborns with citrin deficiency utilizing parameters already in place in present NBS methods. To achieve this goal, we re-analyzed NBS profiles of amino acids and acylcarnitines in 96 NICCD patients, who were diagnosed through selective screening or positive family history. Hereby, we identified the combined evaluation of arginine (Arg), citrulline (Cit), isoleucine+leucine (Ile + Leu), tyrosine (Tyr), free carnitine (C0) / glutarylcarnitine (C5-DC) ratio in DBS as potentially sensitive to diagnose citrin deficiency in pre-symptomatic newborns. In particular, a scoring system using threshold levels for Arg (≥9 μmol/L), Cit (≥ 39 μmol/L), Ile + Leu (≥ 99 μmol/L), Tyr (≥ 96 μmol/L) and C0/C5-DC ratio (≥327) was significantly effective to detect newborns who later developed NICCD, and could thus be implemented in existing NBS programs at no extra analytical costs whenever citrin deficiency is considered to become a novel target disease.journal articl

Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver?Russell syndrome

Silver?Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient’s intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7?Mb duplication at 15q11.2-q13.1 encompassing the Prader?Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS

Persistence to growth hormone treatment and clinical characteristics of pediatric patients with growth hormone deficiency: A retrospective cohort study of data from the Japan Medical Data Center claims database

Limited real-world data are available on persistence to growth hormone replacement therapy (GHRT) in Japan. Therefore, we used the Japan Medical Data Center claims database to retrospectively investigate persistence with GHRT in patients with pediatric growth hormone deficiency (pGHD). We identified 1,020 patients with pGHD treated with GHRT. The mean age at initial diagnosis was 7.5 ± 3.8 years, and we found a bimodal pattern in age, with peaks at 3 and 12 to 13 years of age; the peaks were more pronounced in male patients. After excluding patients with early withdrawal, 1,016 patients were eligible for persistence analysis. The time to initial treatment discontinuation, i.e., the first prescription-free period of 182 days (6 months) or more, for 50% of the patients was 2,526 days, which was similar to that of treatment completion (2,626 days). Most patients persisted with GHRT until they completed treatment, but 24 out of 1,016 (2.4%) had a treatment discontinuation. The mean proportion of days covered was 89.8%. Being female (hazard ratio [95% CI]: 1.85 [1.36–2.51]) and older age at diagnosis (1.50 [1.41–1.60]) were associated with shorter time to discontinuation. This finding suggests that most patients persist with GHRT until puberty. In conclusion, although most Japanese patients with pGHD appear to persist well with GHRT, some complete GHRT before puberty. Additionally, there are patients diagnosed and starting treatment just before puberty. Therefore, continued efforts towards early referral and diagnosis are important