临床遗传学将研究与临床联系起来，为临床遗传学家转化我们对遗传疾病分子基础理解的进展。该杂志发表将医学遗传学研究与临床实践联系起来的高质量研究论文、简短报告、评论和小型评论。特别感兴趣的主题有：• 将遗传变异与疾病联系起来• 基因组重排和疾病• 表观遗传学和疾病• 翻译基因型到表型• 复杂疾病的遗传学• 遗传疾病的管理/干预• 遗传疾病的新疗法• 发育生物学，因为它与临床遗传学有关• 对患有遗传或处于遗传风险中的心理和行为方面的社会科学研究疾病

The journal "Clinical Genetics" aims to bridge clinical research and genetics, advancing our understanding of the molecular basis of genetic diseases. It publishes high-quality research articles, brief reports, reviews, and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest include: • Linking genetic variation to disease • Genomic rearrangements and disease • Epigenetics and disease • Translating genotype to phenotype • Genetics of complex diseases • Management/intervention of genetic diseases • New therapies for genetic diseases • Developmental biology as it relates to clinical genetics • Social science research on the psychological and behavioral aspects of individuals with genetic diseases or at genetic risk.

《Clinical Genetics》期刊致力于将临床研究与遗传学相结合，推动我们对遗传疾病分子基础的理解。该杂志发表高质量的研究论文、简短报告、评论和小型评论，旨在将医学遗传学研究与临床实践相联系。特别关注的主题包括：• 遗传变异与疾病的关联 • 基因组重排与疾病 • 表观遗传学与疾病 • 从基因型到表型的转化 • 复杂疾病的遗传学 • 遗传疾病的管理与干预 • 遗传疾病的新疗法 • 与临床遗传学相关的发育生物学 • 针对遗传疾病患者或处于遗传风险中的个体的心理和行为方面的社会科学研究。

Clinical Genetics

Immune checkpoint inhibitors (ICIs) improve overall survival in patients with advanced gastric cancer (GC). However, the molecular characterization of GC in ICIs responders is unclear. A total of 288 advanced GC patients were included in this study. Next-generation sequencing analysis was performed on tumor tissue and paired blood to screen for somatic mutants in 639 tumor-associated genes. We demonstrated that ARID1A, HER2/3/4, KMT2C/2D, LRP1B, PIK3CA, SPTA1, and TP53 mutations were significantly correlated with high tumor mutation burden (TMB) score, as well as HER2 amplification. For HER2 and PIK3CA mutations types, this relationship was statistically significant with age and TP53 mutation status, which was also found in the CDH1 gene. These results were confirmed by sequencing 873 GC cases in the cBioPortal database. PIK3CA mutations appear to be associated with longer survival in elderly population and TP53 mutant subtypes. For the first time, we found that GC patients ≥60 years old or with TP53 mutated type and PIK3CA mutations were associated with higher TMB and better ICI response. Building upon the age and TP53 mutation status, this study suggested a novel stratification approach to GC patients and explored the correlations between genetic somatic mutations and TMB score.

Jun Yao

Qing You

Xin Zhang

Yu Zhang

Jiapeng Xu

Xiaokai Zhao

Jieyi Li

Xintao Wang

Ziying Gong

Daoyun Zhang

Weijun Wang

<scp>PIK3CA</scp> somatic mutations as potential biomarker for immunotherapy in elder or <scp>TP53</scp> mutated gastric cancer patients

<scp>PIK3CA</scp>体细胞突变作为老年或<scp>TP53</scp>突变胃癌患者免疫治疗的潜在生物标志物

Fig. S1. Electropherograms. (a): Sanger sequencing showing homozygous COQ2 change in patients P1 and P2: NM_015697.7:c.1169G>C; NP_056512.5: p.Gly390Ala (c.1019G>C; p.Gly340Ala, according to KU877220 GenBank sequence). Both related parents were heterozygous for detected mutation. (b): Sanger sequencing showing homozygous COQ6 change in patient P3: NM_182476.2:c.782C>T; NP_872282.1:p.Pro261Leu. Both healthy parents were heterozygous for the same mutation. Table S1. Clinical and genetic data of patients with steroid resistant nephrotic syndrome (SRNS) and COQ2 and COQ6 variants. Table S2. COQ2 and COQ6 variants. Appendix S1. Patients features, Genetic analysis and Yeast studies. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

M. Gigante

S. Diella

L. Santangelo

E. Trevisson

M.J. Acosta

M. Amatruda

G. Finzi

G. Caridi

L. Murer

M. Accetturo

E. Ranieri

G.M. Ghiggeri

M. Giordano

G. Grandaliano

L. Salviati

L. Gesualdo

Further phenotypic heterogeneity of <scp>CoQ10</scp> deficiency associated with steroid resistant nephrotic syndrome and novel <scp>COQ2</scp> and <scp>COQ6</scp> variants

进一步表型异质性的<scp>辅酶Q10</scp>缺乏症与激素抵抗性肾病综合征及新型<scp>COQ2</scp>和<scp>COQ6</scp>变异相关

To the Editor: Homozygous variants in TAF6 gene cause an autosomal recessive intellectual disability syndrome with Cornelia de Lange syndrome (CdLS)-like features, namely Alazami-Yuan Syndrome (ALYUS; MIM#617126). We report the third family with additional ocular and behavioral features (Figure 1A). The proband (VI-8) was seen in the clinic after family members with congenital nystagmus were referred for genetic testing. He is an 18 years old male with moderate intellectual disability, mild dysmorphic features (Figure 1B) and stereotypic behavior involving bilateral repetitive movements of arms and hands, tapping shoulders, twirling of fingers. Movements stop when verbally distracted and he responds with single words. Global developmental delay including speech and stereotypical behavior were noticed in toddler years. He was operated for bilateral inguinal hernia. He is the third child of a consanguineous couple. Bilateral nystagmus was noticed in childhood. His best corrected visual acuity was 0.4 and 0.3 in the right and left eye, respectively. Flash electroretinogram (ERG) recordings of cone and rod function were normal. Ophthalmological evaluation of family members with congenital nystagmus showed decreased visual acuity and impaired cone and rod function on flash ERG. Whole exome sequencing (Centogene, Germany) in the proband (VI-8) and VI-5, VI-6, VII-1 as a trio, revealed two different causative genetic conditions (Figure 1C). Homozygous missense pathogenic variant, c.323T>C; p.(Ile108Thr) in TAF6 (NM_001190415.1) and

Ecenur Tuc

Fuat Baris Bengur

Aslan Aykut

Ozlem Sahin

Yasemin Alanay

The third family with TAF6‐related phenotype: Alazami‐Yuan syndrome

TAF6相关表型的第三家族：Alazami-Yuan综合征

Split hand/foot malformation ( SHFM ) with long‐bone deficiency ( SHFLD , MIM #119100) is a rare condition characterized by SHFM associated with long‐bone malformation usually involving the tibia. Previous published data reported several unrelated patients with 17p13.3 duplication and SHFLD . Recently, the minimal critical region had been reduced, suggesting that BHLHA9 copy number gains are associated with this limb defect. Here, we report on 13 new families presenting with ectrodactyly and harboring a BHLHA9 duplication.

F. Petit

A.‐S. Jourdain

J. Andrieux

G. Baujat

C. Baumann

C. Beneteau

A. David

L. Faivre

D. Gaillard

B. Gilbert‐Dussardier

P.‐S. Jouk

C. Le Caignec

P. Loget

L. Pasquier

N. Porchet

M. Holder‐Espinasse

S. Manouvrier‐Hanu

F. Escande

Split hand/foot malformation with long‐bone deficiency and <scp>BHLHA9</scp> duplication: report of 13 new families

分裂手/足畸形伴长骨缺损及<scp>BHLHA9</scp>重复：13个新家族的报告

It has been suggested that matrix metalloproteinase ( MMP ) polymorphisms are associated with the pathogenesis of aortic aneurysmal diseases. In this study, we conducted a systematic review with an update meta‐analysis to investigate the relationship between MMP family polymorphisms and aortic aneurysmal diseases. We systematically reviewed 24 polymorphisms in 8 MMP genes related to the risk of abdominal aortic aneurysm ( AAA ), thoracic AA or thoracic aortic dissection ( TAD ). A total of 19 case‐control studies with 15 highly studied MMP polymorphisms were included in our meta‐analysis. Our results suggested that MMP2rs243865 , MMP3rs3025058 , MMP13rs2252070 polymorphisms were significantly associated with AAA risk, MMP2rs11643630 , MMP8rs11225395 polymorphisms were correlated with TAD risk, and MMP9rs3918242 under the dominant model could increase AAA risk in hospital‐based subgroup. No associations with aortic aneurysmal diseases were identified for other polymorphisms assessed in our meta‐analysis. In summary, some studied MMP polymorphisms associated with the risk of aortic aneurysmal diseases are potential predictive biomarkers for the clinical application. Moreover, other MMP polymorphisms with limited studies but relevant to aortic aneurysmal formation and progression need further prospective and large investigations to confirm results.

T. Li

Z. Lv

J.‐J. Jing

J. Yang

Y. Yuan

Clin Genet

Matrix metalloproteinase family polymorphisms and the risk of aortic aneurysmal diseases: A systematic review and meta‐analysis

基质金属蛋白酶家族多态性与主动脉瘤疾病风险：系统综述与Meta分析

Identification of a new pathogenic ASTN1 p.R517X (c.1549C>T) variant in a 7-month-old girl using gene sequencing methods and bioinformatics analysis.

Akif Ayaz

Safiye Güneş Sager

Ahmet Sercan Gökşen

Kıvanç Kök

Emine Caliskan

Omar Alomari

Homozygous <scp>ASTN1</scp> Nonsense Variant Linked to Epileptic Encephalopathy: A Detailed Report With Unique Clinical Presentation

<scp>ASTN1</scp> 无义变异纯合子与癫痫性脑病相关：详细报告及独特临床表现

ABSTRACT To assess the suitability of genome sequencing (GS) as the second step in the diagnostics of patients with the features of 11p15.5‐associated imprinting disorders (ImpDis: Silver–Russell syndrome [SRS], Beckwith–Wiedemann syndrome [BWS]), we performed short‐read GS in patients negatively tested for imprinting disturbances. Obtaining a genetic diagnosis for patients with the features of these syndromes is challenging due to the clinical and molecular heterogeneity and overlap, and many patients remain undiagnosed after the currently suggested stepwise diagnostic workup. GS was conducted in 48 patients (SRS features: n = 37 and BWS features: n = 11). The detection rate differed markedly between the ImpDis: although a genetic cause could be identified in 51% of patients referred with SRS features, no pathogenic variants were detected in patients with BWS features. Thus, GS substantially improves the diagnostic yield and broadens the spectrum of overlapping disorders with SRS features. Obtaining a precise molecular diagnosis provides the basis for a personalized clinical management. Our findings support the use of GS as a second‐tier diagnostic tool for patients with growth disturbances, as it addresses all currently known variant types and shortens the diagnostic odyssey.

Luise Kessler

Jeremias Krause

Florian Kraft

Asmaa K. Amin

Gyorgy Fekete

Anna Lengyel

Eva Pinti

Arpad Kovacs

Annette Lischka

Katja Eggermann

Ingo Kurth

Cordula Knopp

Miriam Elbracht

Matthias Begemann

Thomas Eggermann

Diagnostic Use of Genome Sequencing in Patients With 11p15.5 Imprinting Disorder Features: A Pilot Study

11p15.5印记障碍特征患者基因组测序的诊断应用：一项试点研究

ABSTRACT Maternal uniparental disomy of chromosome 14, upd(14)mat, leads to Temple syndrome (TS), an imprinting disorder characterized by pre‐ and postnatal growth retardation, hypotonia, motor delay, joint laxity, and precocious puberty. The occurrence of upd(14)mat is rare, and it may, in even rarer cases, co‐occur with trisomy 14 mosaicism. To date, only 11 live‐born cases have been reported in the literature. We present a newborn girl with severe hypotonia, global developmental delay, feeding difficulties, dysmorphic features, and cardiac malformations. Using trio whole genome sequencing (WGS) no causative sequence or structural variants were detected. As a chromosomal disorder was suspected the data was further analyzed with a pipeline including analysis of UPD and low‐level mosaicism, which revealed upd(14)mat and low level trisomy 14 mosaicism. This study underscores the significance of advanced genetic testing techniques, thorough data interpretation, and expert clinical evaluation in diagnosing rare disorders with complex molecular mechanisms.

Tilde Olsen

Jakob Ek

Mads Bak

Karen Grønskov

Iben Bache

Stense Farholt

Zeynep Tümer

Concomitant Upd(14)mat and Trisomy 14 Mosaicism in a Newborn Detected by Whole Genome Sequencing

通过全基因组测序检测到的新生儿Upd(14)mat与14号染色体三体嵌合现象

ABSTRACT We present a family with two male siblings diagnosed with a newly described digenic myopathy, involving likely pathogenic loss‐of‐function variants in the SRPK3 and TTN genes: hemizygous p.(Pro68ArgfsTer55) and heterozygous p.(Trp14174Ter), respectively. Both siblings experienced prenatal disease onset, characterized by weak fetal movements, but showed significant clinical improvement over two last years of our follow‐up. Key features included early onset, delayed motor development, and prominent axial and proximal weakness, while adult variants' carriers remained asymptomatic, without any myopathic or cardiac manifestations. Lower limb MRI revealed distinctive abnormalities, with different patterns between the siblings: the older brother showed more pronounced involvement of the thigh muscles, while the younger brother exhibited greater changes in the lower leg muscles. Given the early stage of the disease in our patients and the initial changes observed on MRI, we suggest that the semitendinosus and vastus lateralis muscles are primarily involved at the thigh level in SRPK3/TTN ‐myopathy. This case highlights the importance of considering digenic inheritance in neuromuscular disorders and underscores the necessity of comprehensive genetic analysis in similar cases.

Inna Sharkova

Artem Borovikov

Fedor Konovalov

Maria Nefedova

Olga Shchagina

Sergey Kutsev

Aysylu Murtazina

Clinical and Genetic Analysis of Digenic Muscular Dystrophy due to SRPK3 and TTN Variants in Two Siblings

两例同胞中因SRPK3和TTN变异导致的二基因型肌营养不良的临床与遗传学分析

Screening for Lynch syndrome (LS) is essential in colorectal carcinoma (CRC) diagnosis. The hallmark of CRC in LS is mismatch repair (MMR) deficiency, a vital biomarkers assessed by microsatellite instability (MSI) analysis and/or immunohistochemistry (IHC) staining of the MMR proteins in the tumor, that also predict response to immune checkpoint inhibitors. We report two LS patients who developed MMR proficient CRCs. Patient A, with a pathogenic MSH6 germline variant, presented with two MMR discordant CRCs: a rectal MMRd/MSI adenocarcinoma, and a sigmoid MMR proficient (MMRp) and microsatellite stable (MSS) adenocarcinoma, leading to metastasis. While the MMRd/MSI carcinoma was recognized early and showed complete pathologic response after pembrolizumab treatment, the MMRp/MSS adenocarcinoma was underrecognized and poorly responsive to treatment. A second patient, with a pathogenic PMS2 variant, also developed a MMRp CRC. These cases highlight the complex biological pathways in CRC development and the impact of molecular classification on treatment.

Binny Khandakar

Jill Lacy

Joanna A. Gibson

Mismatch Repair Proficient Colorectal Adenocarcinoma in Two Patients With Lynch Syndrome

两名林奇综合征患者中错配修复功能正常的结直肠腺癌

Abbreviation	Clin Genet
Journal Impact	2.99
Quartiles(Global)	GENETICS & HEREDITY(Q2)

ISSN	0009-9163, 1399-0004
h-index	115

Publication Information	Publisher: Wiley-Blackwell Publishing Ltd，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1970，Proportion of original research papers: 88.55%，Self Citation Rate:3.40%， Gold OA Rate: 25.28%
Average review cycle	网友分享经验：一般,3-8周
Average recruitment ratio	网友分享经验：较易

Clinical Genetics

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PIK3CA somatic mutations as potential biomarker for immunotherapy in elder or TP53 mutated gastric cancer patients

Further phenotypic heterogeneity of CoQ10 deficiency associated with steroid resistant nephrotic syndrome and novel COQ2 and COQ6 variants