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In the SAMD9 Gene

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In the SAMD9 Gene Onuma et al. Human Genome Variation (2020) 7:4 https://doi.org/10.1038/s41439-020-0091-5 Human Genome Variation DATA REPORT Open Access MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene Shinsuke Onuma 1, Tamaki Wada1, Ryosuke Araki2, Kazuko Wada2, Kanako Tanase-Nakao3,SatoshiNarumi3, Miho Fukui1,YasukoShoji1,YuriEtani1, Shinobu Ida1 and Masanobu Kawai1,4 Abstract MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype–phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p. Ala1479Ser). MIRAGE syndrome (OMIM #617053) is a recently the disorder. We herein present a case of MIRAGE discovered disorder with multifaceted clinical features, syndrome with a novel de novo missense variant including myelodysplasia, infection, restriction of growth, [NM_017654.4:c.4435 G > T, p.(Ala1479Ser)] in the adrenal hypoplasia, genital phenotypes, and enteropathy1. SAMD9 gene. Additional associated features are developmental retar- The 2-year-old patient was born from healthy non- 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; dation, dysmorphism, chronic lung disease, and central consanguineous Japanese parents. The family history was nervous system abnormalities. MIRAGE syndrome is unremarkable, and his two older sisters are healthy. Fetal caused by a gain-of-function variant in the SAMD9 gene growth restriction was detected at 27 weeks of gestation on the long arm of chromosome 7 (7q21.2), encoding by sonography. The patient was delivered at 31 weeks of sterile alpha motif domain-containing protein 9, which gestation by cesarean section due to fetal distress. His functions in endosome fusion and regulates cell growth in birth weight was 912 g (−3.2 SD), length was 37.8 cm in vitro models1,2. However, the precise mechanisms by (−1.3 SD), and head circumference was 26.6 cm which variants in the SAMD9 gene cause the MIRAGE (−0.3 SD), based on the sex-specific standards stratified phenotype are largely unknown. In addition, a wide range by gestational age in the Japanese population3. The Apgar of phenotypes with a high mortality rate has been impli- scores were 7 and 8 at 1 and 5 min, respectively. He had cated with little understanding of the genotype– ambiguous genitalia (micropenis, hypospadias, and bifid phenotype correlation due to the paucity of genetically scrotum) without signs of female internal genitalia such as diagnosed subjects. Therefore, the accumulation of uterus and vagina at birth (Fig. 1a), and G-banding patient-based knowledge with underlying genetic infor- chromosome analysis revealed a 46, XY karyotype. mation is essential to better understand the clinical out- Accordingly, he was assigned male. Monosomy 7 was not come, its relation to genotype, and molecular insights of noted by G-banding chromosome analysis at birth. His skin was hyperpigmented (Fig. 1b). He was recognized as having adrenal insufficiency based on hormonal mea- Correspondence: Masanobu Kawai ([email protected]) surements (Table 1) and hypoplasia of the adrenal gland 1Department of Gastroenterology, Nutrition, and Endocrinology, Osaka on abdominal sonography. Treatment with hydro- ’ ’ Women s and Children s Hospital, Osaka, Japan cortisone (30 mg/m2/day) and fludrocortisone (0.025 mg/ 2Department of Neonatology, Osaka Women’s and Children’s Hospital, Osaka, Japan day) was initiated with subsequent dose adjustments being Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Japan Society of Human Genetics Onuma et al. Human Genome Variation (2020) 7:4 Page 2 of 4 Fig. 1 Clinical and genetic features of the patient. a, b Photographs of the patient at birth showing ambiguous genitalia (a) and hyperpigmentation (b). c Growth chart of the patient from 0 to 2 years old19. The red circle and square represent the patient’s height and weight, respectively. d Sanger sequences of the SAMD9 gene in the patient and parents. A heterozygous de novo variant (c.4435 G > T; p.Ala1479Ser) was found in the patient. e Homologs of the SAMD9 gene at the A1479 residue, which is conserved across multiple species. Table 1 Laboratory data at birth. Variables Results Reference values (mean ± 2SD) Variables Results Reference values (mean ± 2SD) WBC (×103/µL) 2.9 19.6 ± 11.2 DHEA-S (µg/dL) 63 184 ± 104 Hb (g/dL) 18.1 19.0 ± 4.0 17-OHP (ng/mL) 1.97 4.5 ± 7.6 Plt (×104/µL) 2.7 28.8 ± 10.6 AMH (ng/mL) 16.9 52.3 ± 47.4 Na (mEq/L) 138 143 ± 12 LH (mIU/mL) 0.9 0.39 ± 0.96 K (mEq/L) 4.1 5.3 ± 1.2 FSH (mIU/mL) 1.8 0.96 ± 1.20 BS (mg/dL) 56 63 ± 44 Testosterone (ng/dL) 175.3 85.9 ± 112.6 ACTH (pg/mL) 2540 50.2 ± 13.8 Estradiol (pg/mL) <5 26.1 ± 77.8 Cortisol (µg/dL) 5.6 14.8 ± 3.8 TSH (µIU/mL) 4.89 8.4 ± 9.6 PRA (ng/mL/hr) 84.7 7.62 ± 13.58 FT4 (ng/dL) 0.89 1.00 ± 0.50 Aldosterone (pg/mL) 11.6 726 ± 570 FT3 (pg/mL) 0.87 1.04 ± 0.98 PRA plasma renin activity, DHEA-S dehydroepiandrosterone sulfate, 17-OHP 17-hydroxyprogesterone, AMH anti-Müllerian hormone. Values outside the reference ranges for neonates are underlined. performed based on the clinical and laboratory findings. severe diarrhea, parenteral nutrition was initiated. He Transient thrombocytopenia and leucopenia were detected continues to receive total parenteral nutrition because during the first2monthsoflife,andtherewerenosigns resuming enteral nutrition reignites gastrointestinal symp- suggesting the presence of myelodysplastic syndrome toms. He was administered several cycles of antibiotics (MDS) thereafter. Bone marrow biopsy was not performed. because of recurrent infections, including aspiration Macrocytosis was never found in the peripheral blood. As pneumonia. To prevent recurrent infections, continuous the patient developed intolerance to enteral feeding due to antibiotic prophylaxis with sulfamethoxazole-trimethoprim Official journal of the Japan Society of Human Genetics Onuma et al. Human Genome Variation (2020) 7:4 Page 3 of 4 was initiated. He exhibited several episodes of acute adrenal subjects, accumulation of variant data and clarification of crisis caused by acute infection and/or aspiration and the genotype–phenotype correlation is a requisite to received high doses of hydrocortisone (100 mg/m2/day). He improve medical management of MIRAGE syndrome. To developed hydrocephalus after the episode of adrenal crisis, date, ~40 cases of MIRAGE syndrome have been repor- – and a ventriculoperitoneal shunt was placed at 7 months ted1,2,4,7 18. Although the identified variants are scattered old. He had been repeatedly moved to the intensive care throughout the entire coding sequence with missense unit due to respiratory complications such as aspiration variants being most frequent, in vitro functional assays pneumonia, and a laryngotracheal separation procedure have revealed the consistent growth restriction phenotype was performed at 2 years old. He has received continuous of mutated SAMD9 protein. This suggests that the variant- positive airway pressure (CPAP) support after laryngo- site-based genotype–phenotype correlation has not been tracheal separation. He has never been discharged from the well determined for MIRAGE syndrome, although those hospital since birth. His growth was markedly restricted who have a variant in an arginine residue have been during follow-up (Fig. 1c). He showed severe psychomotor reported to have more severe clinical presentations than developmental delay. He was bedridden and spoke no those possessing non-arginine residues2,7. Thus, the meaningful words at 2 years old. The presence of adrenal accumulation of knowledge regarding novel variants and hypoplasia, ambiguous genitalia, transient thrombocytope- their associated clinical features is essential to better nia, bowel dysfunction, recurrent infections, and failure to understand the variant-site-based genotype–phenotype thrive are consistent with MIRAGE syndrome. correlation in MIRAGE syndrome. Written informed consent for genetic testing was received In addition to the effects of variant site on the clinical from the patient’s parents at 6 months of age. Long-range course of MIRAGE syndrome, there is evidence of the PCR-basedtargetednext-generationsequencing,ascon- clinical impact of additional genetic signatures in ducted previously4, revealed the presence of a heterozygous MIRAGE syndrome, which includes the loss of chromo- missense variant in exon 3 of the SAMD9 gene some 7 on which the SAMD9 gene variant responsible for [NM_017654.4:c.4435 G > T, p.(Ala1479Ser)]. This variant MIRAGE syndrome is present1,2. Many patients develop was confirmed by Sanger sequencing (Fig. 1d). Sanger transient anemia and thrombocytopenia, but become sequencing of the region containing the identified variant susceptible to the development of MDS when hemato- revealed that this variant was not observed in the parents poietic cells acquire monosomy 7 as an aneuploidy (Fig.
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