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MAB21L2 基因变异致小眼畸形 2 例及 MAB21L1 和 MAB21L2 的基因型 - 表型的系统回顾研究

Two cases of microphthalmia caused by MAB21L2 gene mutation and a systematic review of genotypephenotype associations of MAB21L1 and MAB21L2

来源期刊: 眼科学报 | 2024年2月 第39卷 第2期 75-83 发布时间:2024-02-28 收稿时间:2024/6/5 11:00:53 阅读量:1255
作者:
关键词:
先天性小眼球MAB21L2基因MAB21L1基因突变热点
microphthalmia MAB21L2 gene MAB21L1 gene mutation hotspots
DOI:
10.12419/24011805
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目的:总结MAB21L2基因的变异和临床特点,并与高度同源的MAB21L1基因进行比较。 方法:对中山眼科中心临床基因数据库中MAB21L2基因变异患者进行基因型和表型分析,回顾性分析既往文献报道MAB21L2基因和高度同源基因MAB21L1变异的表型-基因型的关系。结果:在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带已知变异c.151C>G/p.(Arg51Gly),患者双眼小眼畸形伴虹膜脉络膜缺损,伴骨关节屈曲。母亲携带相同杂合变异但表型正常;先证者2携带未报道的变异c.1042G>T/p.(Glu348*),左眼小眼畸形,右眼正常且无全身异常。结合文献回顾发现,在显性遗传模式下,80%的MAB21L2杂合致病变异(20/25)和100%的MAB21L1杂合致病变异(25/25)发生在氨基酸49-52 区域,导致小眼无眼或眼缺损异常(microphthalmia, anophthalmia or coloboma,MAC);携带该区域MAB21L2基因杂合突变的患者除MAC外,部分还伴骨骼关节发育异常(12/24,50%);杂合截短变异发生在MAB21L2基因可导致MAC(5/5,100%),而发生在MAB21L1则不致病。 结论:在2个小眼畸形家系中发现了MAB21L2因1个新致病变异和1个已知热点致病变异,通过文献综述比较和总结了MAB21L1MAB21L2基因的突变频谱以及基因型-表型相互关系,为此类基因缺陷导致遗传病的诊断和鉴别诊断提供依据。
Objective: To summarize the genetic variations and clinical features of the MAB21L2 and compare them with the highly homologous MAB21L1 gene. Methods: A genotype -genotype analysis was performed on the patients with MAB21L2 gene variants in the clinical genetic database of Zhongshan Ophthalmic Center, Sun Yat-sen University. A retrospective review was undertaken to analyze the phenotype-genotype correlations of MAB21L2 gene variants and the highly homologous MAB21L1 gene variants reported in the previous literature. Results: Two heterozygous MAB21L2 gene variants were identified in two families with microphthalmia: Proband 1 carried the known variant c.151C>G/p.(Arg51Gly), presenting with bilateral microphthalmia with iris-choroidal coloboma and flexion of joints. The mother carried the same heterozygous variant but had a normal phenotype. Proband 2 carried the unreported variant c.1042G>T/p.(Glu348*), manifesting as left-sided microphthalmia with a normal right eye and no other systemic abnormalities. Through literature review, we found that under a dominant inheritance pattern, 80% of heterozygous pathogenic MAB21L2 variants (20/25) and 100% of heterozygous pathogenic MAB21L1 variants (25/25) occurred in the amino acid region 49-52, resulting in microphthalmia, anophthalmia, and coloboma (MAC). Some patients with heterozygous MAB21L2 variants in this region exhibited additional skeletal and joint dysplasia (12/24, 50%). Heterozygous truncating variants in MAB21L2 led to MAC (5/5, 100%), while those in MAB21L1 were non-pathogenic. Conclusions: This study identified a novel pathogenic variant and a known hotspot pathogenic variant of MAB21L2 in two families with microphthalmia. Through a comprehensive literature review, we compared and summarized the mutation spectrums and genotype-phenotype correlations of MAB21L1 and MAB21L2 genes, providing valuable insights for the diagnosis and differential diagnosis of genetic diseases caused by these gene defects.

文章亮点

1. 关键发现

报道了 MAB21L2 新的截短致病变异 c.1042G>T/p.(Glu348*),通过对两高度同源基因 MAB21L1MAB21L2 的比较,总
结出两基因变异和表型的异同点,尤其是氨基酸 49-52 区域变异表型的差异。通过全外显子测序证实 c.151C>G/p.(Arg51Gly)
变异的嵌合情况。

2. 已知与发现

已知:MAB21L1 隐性遗传时导致小脑 - 眼 - 颅面 - 生殖系统发育异常,显性遗传时导致小睑裂 - 眼前节 - 黄斑发育不全;
MAB21L2 变异常导致眼和骨关节发育异常。
发现:在氨基酸 49-52 区域,MAB21L2 杂合致病变异相较于 MAB21L1 杂合变异除导致小眼无眼或眼缺损异常外,还可
伴骨骼关节发育异常;MAB21L2 杂合截短变异致病。

3. 意义与改变

新的截短致病变异拓展了 MAB21L2 的突变频谱;为两基因 MAB21L1MAB21L2 缺陷导致遗传病的诊断和鉴别诊断提
供依据。

    先天性小眼球(microphthalmia)指眼球总轴长至少低于平均年龄水平两个标准差,发病率大约为1/7 000;无眼球(anophthalmia)指眼附属器存在的情况下缺少整个眼球,发病率大约为1/30 000;眼球缺损(coloboma)指眼球发育过程中,因视裂闭合不全导致从视盘、视网膜和脉络膜(眼后段)到睫状体、晶状体和虹膜(眼前段)中任何部位的眼组织缺损,发病率大约为1/5 000[1-2]。三者均是结构上存在缺陷的先天性眼畸形,常常伴随发生因此合并称为MAC(microphthalmia, anophthalmia or coloboma, 小眼无眼或眼缺损异常)[3-4]。致病因素有环境因素和遗传因素,目前已知相关的致病基因至少有82个,可以解释约60%先天性小眼球和无眼球病例的致病原因[1, 4-6]
MAB21L2基因(MIM 615877)位于染色体4q31.1区,仅有1个外显子,由1 080个碱基编码359个氨基酸,是MAB21家族成员之一。该基因在眼睛、大脑、心脏、肝脏等器官的发育过程中具有调节作用[7-9],其基因变异可导致显性或隐性遗传的先天性小眼球,伴或不伴有骨骼或关节的发育异常[10]。回顾既往文献,目前已知MAB21L2基因缺陷病例有11个家系25例患者,仅有一个家系来自中国[11]MAB21家族另一个成员,MAB21L1基因(MIM 601280),与MAB21L2基因高度同源,其纯合致病变异可导致常染色体隐性遗传的小脑-眼-颅面-生殖器综合征,杂合致病变异可导致小睑裂-眼前节-黄斑发育不全综合征[12-13]。两个基因变异的很多患者都有MAC表型,二者所致表型的差异需要进一步鉴别。本文报道了2个携带MAB21L2基因变异的MAC家系,总结了MAB21L2基因的变异特点和临床特点,并与MAB21L1基因的变异和临床特点进行比较。

1 资料和方法

1.1 一般资料

对中山大学中山眼科中心临床基因数据库进行基因致病性分析,基于眼遗传病患者全外显子测序(whole exome sequencing,WES)的变异数据,筛查携带MAB21L2基因(NCBI RefSeq: NM_006439.5/NP_006430.1)潜在变异位点的家系。详细询问先证者及其家系成员的全身病史、家族史和婚育史并予以记录。本研究遵循《赫尔辛基宣言》,经中山眼科中心伦理委员会审核批准(批件号:2011KYNL012),先证者及其家属对本研究目的知情并自愿签署知情同意书。

1.2 方法

1.2.1 基因变异致病性分析
通过多步骤生物信息学工具对MAB21L2基因变异位点进行致病性预测,包括SIFT (http://sift.jcvi.org/)、Polyphen-2(http://genetics.bwh.harvard.edu/pph2/)、PROVEAN (http://provean.jcvi.org/seq_submit.php)、CADD(http://cadd.gs.washington.edu)和 REVEL (https://sites.google.com/site/revelgenomics/),并与gnomAD(The Genome Aggregation Database,基因组聚合数据库,https://gnomad.broadinstitute.org,2023.04查阅)数据库进行比较验证,参考人类基因突变数据库(The Human Gene Mutation Database,HGMD,2022.04版),并根据美国医学遗传和基因组学学会 (American College of Medical Genetics and Genomics,ACMG)指南进行致病性分级。对存在MAB21L2基因致病变异的样品进行82个已知先天性小眼畸形基因变异的致病性分析[6]
1.2.2 基因组测序
对先证者1母亲的基因组DNA样本进行WES,操作参照文献[14]。通过文库构建和外显子捕获后,采用MGI2000高通量测序仪进行测序。样品平均测序深度>100×,过滤测序深度低于10的读数(reads)数据后,将测序数据与UCSC hg19的基因组序列进行比对,对获得的单核苷酸多态或其他变异进行致病性分析,方法同前述。用在线工具IGV(https://igv.org/ 2.12.2版)对WES数据进行可视化分析。
1.2.3 Sanger测序验证和共分离验证
使用primer3(https://primer3.ut.ee)分别设计MAB21L2基因变异位点的上下游PCR引物,c.151C>G位点的正向引物序列:5′-GTGTATAGCCCGGACCTGTG-3′,反向引物序列:5′-CTCAAATTCGGTGGGCGAAA-3′;c.1042G>T位点的正向引物序列:5′-CAGCCGCTCAACAACTACCA-3′,反向引物序列:5′-TTTTCAAGCAGTCCCCAGCA-3′。 使用PCR仪(美国,Bio-Rad)进行PCR扩增,反应条件:95℃预变性5 min;95 ℃变性30 s,58 ℃退火及延伸30s,35个循环。使用测序仪3130XL(美国,ABI),对筛选出携带MAB21L2致病变异患者及可能的家系成员进行 Sanger 测序验证,最后使用SnapGene软件(6.1.1版,美国,Insight Science)进行序列比对和家系共分离分析。
1.2.4 临床资料收集
收集患者病历资料,并对患者及可能家系成员进行常规的眼科检查和全身检查:眼外观、裂隙灯显微镜(BQ900,英国海克-斯特莱特公司)、眼轴长度、角膜大小、验光、视力、彩色眼底照相仪(CR-2 Plus AF,日本佳能公司)、光学相干断层扫描(optical coherence tomography,OCT)(iVUE 100,美国光视公司)、激光扫描检眼镜检查(Daytona,英国欧堡公司)、超声生物显微镜检查(SW-3200L,天津索维公司)以及下肢的X线检查。
1.2.5 MAB21L1MAB21L2基因文献综述
分别以“MAB21L1”和“MAB21L2”为检索词,在PubMed(https://pubmed.ncbi.nlm.nih.gov)和中国知网(https://www.cnki.net)中检索,结合HGMD(https://www.hgmd.cf.ac.uk/ac/search.php)纳入有MAB21L1MAB21L2基因变异患者的文献。根据ACMG指南评估致病性并绘制两个基因的变异频谱。将所有患者表型按眼部异常和全身异常排列比较。

2 结果

2.1 致病变异

中山眼科中心临床基因数据库包含10 530个无亲缘关系眼遗传病先证者的全外显子数据库(包括WES和靶向外显子测序),在2个小眼畸形家系中发现2个MAB21L2基因杂合变异:先证者1携带MAB21L2已知致病变异c.151C>G/p.(Arg51Gly),该变异引起第151位点的碱基C被G代替,导致第51位精氨酸替换为甘氨酸。在gnomAD数据库中未发现该位点存在,同时在多种变异预测工具中预测为有害变异。既往有2个小眼畸形家系报道该变异[11, 15],属于突变的热点区域,体内功能试验表明该突变会导致斑马鱼眼球和晶状体的异常发育,体外试验证实突变体表达的蛋白数量降低,稳定性下降[15]。Clinvar数据库收录了这个变异(VCV000427785.4),分类为致病的(两颗星)。先证者1的父母、哥哥进行了该位点的验证,母亲携带相同的MAB21L2基因杂合变异c.151C>G,其余家系成员在该位点未见异常(图1A);根据ACMG指南,该位点为致病变异P(PS1+PS3+PM1+PM2+PP3+PP4+BS4)。母亲基因组DNA的WES平均测序深度为126×,一共有160条reads覆盖MAB21L2基因c.151这个碱基,其中31条reads在c.151显示为G,129条reads在该点显示为C,等位基因的杂合比为19.38%(31/160)(图1A)。先证者2携带一个未被报道的变异c.1042G>T/p.(Glu348*),该变异引起第1 042位点的碱基G被T代替,导致第348位谷氨酸发生无义变异,引起终止密码子的提前出现。在gnomAD数据库中未发现该位点存在,根据ACMG指南判断,该变异判定为可能致病变异LP(PM2+PM4+PM6+PP4)(图1B)。WES排除2名先证者及先证者1的母亲在其他82个导致先天性小眼畸形相关基因编码区内存在致病性点突变或可能的结构变异。

2.2 表型特征

先证者1,女,足月顺产,无吸氧史,出生体质量在正常范围,2岁时因视物不清,于2013年10月18日在中山眼科中心就诊,首诊记录双眼先天性小角膜、眼球震颤、瞳孔易位、斜视、视力差和双腿膝关节呈屈曲状态。12岁随访时,患儿身高148 cm,体质量41 kg,双眼视力指数,双眼水平性眼球震颤,左眼内斜视,右眼角膜直径5.0 mm,左眼角膜直径4.5 mm,左眼角膜混浊,双眼瞳孔向鼻下方移位并伴有下方虹膜缺损,右眼晶状体透明,左眼因角膜混浊晶状体窥不清,双眼脉络膜下方缺损;全身检查发现,患者站立和行走时双腿关节屈曲难以伸直,X线片显示股骨和胫骨夹角约呈130°(图2A);生殖系统和智力未见明显异常。先证者1母亲,女,43岁,身高153 cm,体质量55 kg,双眼裸眼视力均为0.8,角膜透明,双侧瞳孔等大等圆对光反射灵敏,虹膜无缺损,双眼晶状体在位且透明,眼底检查发现视盘椭圆形、淡红色、边界清晰,动静脉管径之比为2∶3,可见中心凹反光,眼底呈均匀深橘红色,未见脉络膜缺损,站立和行走时未见关节屈曲异常(图2B),全身未见明显异常;先证者1的父亲和哥哥眼睛及全身未见明显异常(图2C、D)。先证者2,女,病历记录显示出生后左眼小眼畸形,右眼正常,未记录双眼晶状体情况,全身系统未发现其他明显异常,该家系因失访未行进一步检查。

2.3 MAB21L1MAB21L2基因的变异和临床特点比较

MAB21L1MAB21L2基因各有6篇文献符合分析要求,共包含21个MAB21L1家系的38例患者(AD:25例;AR:13例)和11个MAB21L2家系的25名患者(AD:23例;A R:2例),见表1和附表。结合本研究中的2个家系的2名先证者和1名不全外显子携带者,对34个家系的65例患者进行基因型-表型分析发现(图3):在显性遗传模式下,80%的MAB21L2变异(20/25)和100%的MAB21L1变异(25/25)发生在氨基酸49-52 区域,68%的致病变异集中在51位点精氨酸(R)(34/50)。在MAB21L1基因中,51R变成谷氨酰胺(Q)8例(c.152G>A)、亮氨酸(L)6例(c.152G>T)、脯氨酸(P)1例(c.152G>C),患者均表现为MAC不伴全身异常(图3A);在MAB21L2基因,51 R变成半胱氨酸(C)2例(c.151C>T)、甘氨酸(G)8例(c.151C>G)、组氨酸(H)9例(c.152G>A),患者表现为MAC伴骨骼关节发育异常,其中51位点精氨酸(R)替代为半胱氨酸(C)的时候症状最为严重,表现为无眼症、严重的骨骼发育不良、近端骨短缩和智力障碍[10, 16](图3B);本文先证者1所携带的c.151C>G,在既往文献中导致2个家系7例患者的眼部异常和骨关节发育异常[11, 15],在其中一个3代家系中,Sanger测序显示第一代的母亲于该位点存在肉眼几乎不可分辨的杂合G峰,家系图上该样本被标注野生型(WT)[15]。值得注意的是,本文先证者1的母亲携带同先证者1相同的杂合峰c.151C>G,但眼部和骨关节未见明显异常。WES显示,母亲在c.151等位基因杂合比为19.38%(31/160),本研究首次证实了c.151C>G变异的嵌合情况。此外,杂合的截短变异对MAB21L1MAB21L2的临床表型影响相差甚远:发生在MAB21L1的杂合截短变异不致病,而发生在MAB21L2的杂合截短变异表现为不伴全身异常的MAC(5/5,100%),其中3人单眼发病,2人双眼发病[1, 17-18]。而携带MAB21L2基因错义致病变异的患者均为双眼发病。在常染色体隐性遗传模式下,MAB21L1的变异导致角膜变性常伴有全身异常,其临床表现主要包括角膜混浊(11/13,85%)、外生殖器发育不全(11/13,85%)、生长发育迟缓(9/11,82%)、中枢神经系统发育异常(9/11,82%)等全身异常;而MAB21L2的纯合变异主要表现为MAC(2/2,100%),或轻度骨发育异常。见表1。
图1 2例MAB21L2基因变异的家系图和Sanger测序图
Figure1 Pedigrees and Sanger sequence consequences of two family with MAB21L2 variants
(A)家系1的家系图(左)、Sanger测序图(中)、母亲WES数据IGV可视化图(右);(B)家系2的家系图(左)和Sanger测序图(右)。
:正常男性;○:正常女性;●:女性患者;⊙:女性携带者;↗□:先证者;NC:正常对照;M:变异。
(A) Family pedigree 1 (left), Sanger sequencing chromatogram (middle), and Maternal exome sequencing data visualization using IGV (Integrative Genomics Viewer) (right). (B) Sanger sequence consequences and the pedigree of family 2. □: normal male; ○: normal female; ●female patient; ⊙: female carrier; ↗□: proband; NC: normal control; M: mutant.
图2 家系1先证者及其家属成员的表型特征
Figure 2 The phenotypic characteristics of the proband and family members in Pedigree 1
(A)先证者1(II:2)的眼前段照片、超声生物显微镜检查、扫描激光眼底检查以及直立状态下下肢正侧面照和X线片;(B)先证者1母亲(I:2)的眼前段照片和彩色眼底照片以及直立状态下下肢正侧面照;(C)家系1(I:1)未携带变异家系成员的眼前段照片和彩色眼底照相,(D)家系1(II:1)未携带变异家系成员的眼前段照片和彩色眼底照相。 (A) Anterior segment photograph, ultrasound biomicroscope examination, scanning laser fundus imaging, frontal and lateral photographs of the lower limbs in an upright position, and X-ray of the proband 1 (II:2); (B) The anterior segment, color fundus photographs, and frontal and lateral photographs of the lower limbs in an upright position of the proband1's mother (I:2); (C) The anterior segment and color fundus photographs of family members without genetic variants in pedigree 1 (I:1); (D) The anterior segment and color fundus photographs of family members without genetic variants in pedigree 1 (II:1).
图3 MAB21L1MAB21L2基因型-表型的比较
Figure 3 Genotype-phenotype comparison between MAB21L1 and MAB21L2
(A) MAB21L1基因型和表型特征;(B)MAB21L2基因型和表型特征;AD:显性遗传变异,AR:隐性遗传变异,MAC:小眼、无眼、眼缺损,骨骼关节发育异常(skeletal joint dysplasia,SJD),智力障碍(intellectual disability,ID), +:疾病的严重程度。错义变异用黑色柱子(I)表示,截短变异用红色柱子(I)表示,红色字体表示本文报道的先证者。 (A) Genotype and phenotypic characteristics of MAB21L1. (B) Genotype and phenotypic characteristics of MAB21L2. MAC: microphthalmia, anophthalmia, coloboma. SJD: skeletal joint dysplasia. ID: intellectual disability. +: the severity of the disease. Missense variants were represented by black columns (I), truncating variants by red columns (I). The two probands reported in this paper were indicated in red font.

3 讨论

本研究发现了2个MAB21L2基因变异引起的MAC家系。先证者1携带已知基因变异c.151C>G,该变异位点位于MAB21L2显性致病变异的热点位置,患者表现明显的因先天发育异常引起的眼球缺损、小角膜等眼部症状以及出生即伴有的关节屈曲的全身异常,先证者1的母亲携带MAB21L2相同变异c.151C>G,变异杂合比为19.38%,但无明显的表型异常;先证者2携带未报道过的杂合变异c.1042G>T,该变异位点位于MAB21L2显性致病变异的非热点位置,患者表现为单眼的先天性小眼畸形而不伴明显的其他系统异常。研究者最初在秀丽杆状线虫中发现(male abnormal gene family 21,MAB21)家族基因能决定细胞命运[19]。后续多项研究发现该家族基因在脊椎动物中高度保守,对眼睛、大脑、生殖器官、骨骼等的发育起着重要的作用[7, 9, 20-22]MAB21家族目前已知的成员包括:MAB21L1-3,仅MAB21L1MAB21L2被在线人类孟德尔遗传数据库收录(MIM 601280和MIM 615877)。两个基因在序列上存在94%同源性,在晶状体的发育过程中起到关键作用,致病突变导致的临床表型均涉及眼部结构功能异常[8, 23]。既往研究发现,MAB21L2变异可以导致显性或隐性的先天性小眼球,伴或不伴有骨骼或关节的发育异常[10]MAB21L1基因纯合致病变异可导致常染色体隐性遗传的小脑-眼-颅面-生殖器综合征[13]。笔者在前期研究中发现,发生在MAB21L1突变热点区域的杂合变异(p.51-52),可导致新的眼发育异常——小睑裂-眼前节-黄斑发育不全综合征(blepharophimosis, anterior segment and macular dysgenesis, BAMD)[12]。眼睛发育异常类似的情况在MAB21L2突变热点区域也可以观察到。MAB21的p.51-52分别为精氨酸和苯丙氨酸,在MAB21家族内及不同物种间都高度保守[12, 24]。本文系统回顾了携带2个基因在p.51-52及邻近区域杂合突变患者的临床表型发现,MAB21L2MAB21L1在氨基酸49-52区域的杂合突变均会导致MAC,MAB21L2基因热点区域杂合突变的患者除MAC外部分还伴骨骼关节发育异常(12/24,50%)(表1)。值得注意的是,在MAB21L2基因51位精氨酸(R)被不同的氨基酸突变替代会导致不同严重程度的表型(半胱氨酸>甘氨酸/组氨酸,C>G/H)(图3B),突变为半胱氨酸对应的表型最为严重,但在MAB21L1中未曾发现类似差异。在Polyphen2预测评分中,精氨酸(R)替代为半胱氨酸(C)时,分值最高为1,替代为甘氨酸/组氨酸(G/H)时均为0.99。既往也有其他疾病由于错义变异导致替代或产生半胱氨酸时症状更加严重,比如马方综合征相关的晶体脱位[25]MAB21L2基因中精氨酸替代为半胱氨酸时症状更严重的具体原因还需要进一步的研究。本文报道的51位点精氨酸(R)替代为甘氨酸(G)的表型相对轻微,除MAC外,仅伴有轻微的关节屈曲,先证者1与既往一个携带同样变异的中国家系表型相似[11]。先证者1的母亲虽然携带相同致病位点c.151C>G,但是其角膜、虹膜、脉络膜和视网膜都无明显异常,也未见明显全身异常,WES显示母亲在该位点的等位基因杂合比为19.38%,这可能是母亲无明显表型的原因。

表1 MAB21L1MAB21L2的变异和临床表型的统计占比

Table 1 The statistical proportion of variants and phenotypes in MAB21L1 and MAB21L2

由于MAB21L1MAB21L2两个基因的高度同源性、两个基因的变异频谱在热点区域的一致性以及在基因变异后表型方面都有MAC,所以两个基因变异所导致的表型需要进一步的鉴别诊断。MAB21L1在热点区域杂合变异导致的表型局限在眼睛,除了典型的MAC外,还常伴有晶体发育的异常(19/21,90%)[7, 24, 26];其在非热点区域杂合的截短变异不致病。MAB21L2在热点区域杂合变异在眼部表型集中表现为MAC,常伴有骨骼关节发育的异常(表1);在非热点区域的杂合截短变异,仅伴有眼部的MAC表型,并且多为单眼发病(附表)。MAB21L1隐性遗传模式下除了眼部的表型外,还伴外生殖器发育异常、小脑发育异常、生长发育迟缓等全身发育的异常[13]MAB21L2的双位点纯合变异表现为MAC,伴或不伴轻微的骨发育异常[10]。通过两个基因变异所致表型的差异,可以为临床医生的诊断提供参考价值。综上所述,本研究报道的一个新的截短变异c.1042G>T/p.(Glu348*),拓宽了MAB21L2变异频谱;报道了一个携带变异热点c.151C>G的家系并首次观察到热点区域突变不全外显现象。通过文献回顾分析总结两高度同源基因MAB21L1MAB21L2基因型-表型之间的异同点,这些结论从分子遗传学角度提供帮助,有助于临床医生对相关疾病的诊断和鉴别诊断。

利益冲突

所有作者均声明不存在利益冲突。

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附表:MAB21L1MAB21L2致病变异和临床表型 supplymentary table: variants and phenotypes in MAB21L1 and MAB21L2.

致病基因 变异 蛋白改变 gnomAD AF REVEAL CADD HGMD ACMG分级 ACMG证据 文献中ID 眼部表型 其他系统异常 文献PMID
MAC
角膜混浊
晶体异常
眼球震颤
骨关节发育异常
外生殖器发育不全
生长发育迟缓
中枢神经系统异常
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS3+PM1+PM2+PP1+PP3+PP4
F1-1A
OU
/
OU
+
/
/
/
/
33973683
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS2+PS3+PM1+PM2+PP1+PP3+PP4
F1-1B
OU
/
OU
/
/
/
/
/
33973683
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS2+PS3+PM1+PM2+PP1+PP3+PP4
F1434-II1
OU
/
OU
+
/
/
/
/
36413568
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS2+PS3+PM1+PM2+PP1+PP3+PP4
F3413-I1
OU
NA
NA
NA
NA
NA
NA
NA
36413568
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS2+PS3+PM1+PM2+PP1+PP3+PP4
Family3-II:2
OU
/
OU
+
/
/
/
/
36892533
MAB21L1
c.[152G>T];[=]
p.[R51L];[=]
/
0.682
29.6
DM
P
PS1+PS2+PS3+PM1+PM2+PP1+PP3+PP4
Family4-II:2
OU
/
OU
+
/
/
/
/
36892533
MAB21L1
c.[152G>C];[=]
p.[R51P];[=]
/
0.694
31
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F592-II:1
OU
/
OU
+
/
/
/
/
36413568
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
Family1-II:1
OU
/
OU
+
/
/
/
/
36892533
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
Family1-III:1
OU
/
OU
+
/
/
/
/
36892533
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
Family2-II:1
OU
/
NA
+
/
/
/
/
36892533
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F96571-II1
OU
OS
NA
/
/
/
/
/
36413568
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F96571-II2
OU
OD
/
+
/
/
/
/
36413568
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F511-II1
OU
OU
OS
+
/
/
/
/
36413568
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F511-III1
OU
/
/
+
/
/
/
/
36413568
MAB21L1
c.[152G>A];[=]
p.[R51Q];[=]
/
0.542
30
/
P
PS2+PM1+PM2+PM5+PP1+PP3+PP4
F511-III2
OU
/
OU
+
/
/
/
/
36413568
MAB21L1
c.[155T>G];[=]
p.[F52C];[=]
/
0.745
32
/
LP
PM1+PM2+PP1+PP3+PP4
Family5-II:3
OU
OD
OU
+
/
/
/
/
36892533
MAB21L1
c.[155T>G];[=]
p.[F52C];[=]
/
0.745
32
/
LP
PM1+PM2+PP1+PP3+PP4
Family5-III:1
OU
/
OU
/
/
/
/
/
36892533
MAB21L1
c.[155T>G];[=]
p.[F52C];[=]
/
0.745
32
/
LP
PM1+PM2+PP1+PP3+PP4
F5531-I:1
OU
NA
NA
NA
NA
NA
NA
NA
36413568
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-II4
OU
/
OU
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-II7
OU
OD
+
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-III1
OU
/
+
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-III2
OU
/
+
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-III3
OU
/
OU
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-III4
OU
/
+
+
/
/
/
/
36446583
MAB21L1
c.[156C>G];[=]
p.[F52L];[=]
/
0.334
24.7
/
P
PS3+PM1+PM2+PP1+PP3+PP4
F-III5
OU
/
+
+
/
/
/
/
36446583
MAB21L1
c.[184C>T];     
[68T>C]
p.[R62C];[-]
0.000038885;
/
0.585;/
31;/
DM?;/
B;/
PP3+BS2+BS4;/
F2-2
OS
/
OD
/
/
/
/
/
33973683
MAB21L1
c.[658G>C];
[*529A>G]
p.[G220R];[-]
0.00000402;/
0.446;/
26.2;/
DM?;/
VUS;/
PP1+PP3+BS2;/
F3-3
OU
/
/
/
/
/
/
/
33973683
MAB21L1
c.[698A>C]; 
[698A>C]
p.[Q233P];
[Q233P]
/
0.332
25.1
DM
VUS
PM2+PP4
F2-II3
/
+
/
+
/
+
NA
CH
30487245
MAB21L1
c.[279_286del
ACTGCCCG];
[279_286delAC
TGCCCG]
p.[P95Rfs*47];
[P95Rfs*47]
/
/
/
DM
P
PVS1+PM2+PP4
F3-II3
/
+
/
/
/
+
+
CH
30487245
MAB21L1
c.[735dupG];
[735dupG]
p.[C246Lfs*18];
[C246Lfs*18]
/
/
/
DM
P
PVS1+PM2+PP4
F1-II3
/
+
/
+
/
+
+
CH
27103078
MAB21L1
c.[840C>G];
[840C>G]
p.[Y280*];   
[Y280*]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F5-IV1
/
+
/
+
/
+
+
CH
30487245
MAB21L1
c.[840C>G];
[840C>G]
p.[Y280*];   
[Y280*]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F5-VI4
/
+
/
+
/
+
+
CH
30487245
MAB21L1
c.[840C>G];
[840C>G]
p.[Y280*];   
[Y280*]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F5-VI5
/
+
/
+
/
+
+
CH
30487245
MAB21L1
c.[841delG];
[841delG]
p.[E281Sfs*20];
[E281Sfs*20]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F1-VI2
/
+
/
+
/
+
+
CH
30487245
MAB21L1
c.[841delG];
[841delG]
p.[E281Sfs*20];
[E281Sfs*20]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F1-VI5
/
+
/
+
/
+
+
NA
30487245
MAB21L1
c.[841delG];
[841delG]
p.[E281Sfs*20];
[E281Sfs*20]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F1-VI6
/
+
/
+
/
+
NA
NA
30487245
MAB21L1
c.[841delG];
[841delG]
p.[E281Sfs*20];
[E281Sfs*20]
/
/
/
DM
P
PVS1+PM2+PP1+PP4
F1-VI7
/
+
/
+
/
+
+
CH
30487245
MAB21L1
c.[859delC];
[859delC]
p.[R287Efs*14];
[R287Efs*14]
/
/
/
DM
P
PVS1+PM2+PP4
F4-V1
/
+
/
+
/
+
+
CH
30487245
MAB21L2
c.[145G>A];[=]
p.[E49K];[=]
/
0.836
32
DM
LP
PM1+PM2+PM6+PP3+PP4+PP5
F131-II1
OU
/
/
/
S
/
/
/
24906020
MAB21L2
c.[151C>T];[=]
p.[R51C];[=]
/
0.868
32
DM
P
PS2+PS3+PM1+PM2+PP3+PP4+PP5
F676-II1
A
/
/
/
JC,SL
/
/
ID
24906020
MAB21L2
c.[151C>T];[=]
p.[R51C];[=]
/
0.868
32
DM
P
PS2+PS3+PM1+PM2+PP3+PP4+PP5
F4480-II1
A
/
/
/
JC,SL
/
/
ID
24906020
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
II-7
OU
/
+
+
JC
/
/
/
25719200
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
II-1
OU
/
+
+
JC
/
/
/
25719200
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
II-5
OU
/
+
+
JC
/
/
/
25719200
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
III-1
OU
/
+
+
JC
/
/
/
25719200
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
III-2
OU
/
+
+
JC
/
/
/
25719200
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
P
PS1+PM1+PM2+PP3+PP4+PP5
F1P1-III1
OU
/
/
/
JC
/
/
/
35929935
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
P
PS1+PM1+PM2+PP3+PP4+PP5
F1P2-II1
OU
/
/
/
JC
/
/
/
35929935
MAB21L2
c.[151C>G];[=]
p.[R51G];[=]
/
0.851
29.8
DM
P
PS1+PS3+PM1+PM2+PP3+PP4+BS4
F1-II2
OU
OS
NA
OU
JC
/
/
/
本文
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-III1
OU
/
/
/
JC
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-I1
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-II1
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-II5
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-II6
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-III2
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-III10
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-III11
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[152G>A];[=]
p.[R51H];[=]
/
0.879
32
DM
LP
PM1+PM2+PM5+PP1+PP3+PP4+PP5
F1463-III12
+
/
/
/
/
/
/
/
24906020
MAB21L2
c.[1A>C];[=]
p.[M1?];[=]
/
/
/
DM
LP
PM2+PM4+PP4+PP5
P40 
OU
/
/
/
/
/
/
/
32737437
MAB21L2
c.[1A>C];[=]
p.[M1?];[=]
/
/
/
DM
LP
PM2+PM4+PP4+PP5
P40-father
OU
/
/
/
/
/
/
/
32737437
MAB21L2
c.[379A>T];[=]
p.[K127*];[=]
/
/
/
DM
VUS
PM2+PM4+PP4
16–1
U
/
/
/
/
/
/
/
36192130
MAB21L2
c.[840C>G];[=]
p.[Y280*];[=]
/
/
/
DM
VUS
PM2+PM4+PP4
P14DG0332
U
/
/
/
/
/
/
/
29450879
MAB21L2
c.[1042G>T];[=]
p.[E348*];[=]
/
/
/
/
LP
PM2+PM4+PM6+PP4
F1-I1
OS
NA
NA
NA
NA
NA
NA
NA
本文
MAB21L2
c.[740G>A];
[740G>A]
p.[R247Q];
[R247Q]
/
0.826
33
DM
VUS
PM2+PP3+PP4+PP5
F4468-II1
OU
/
/
/
/
/
/
/
24906020
MAB21L2
c.[740G>A];
[740G>A]
p.[R247Q];
[R247Q]
/
0.826
33
DM
VUS
PM2+PP3+PP4+PP5
F4468-II2
OU
/
/
/
MSL
/
/
/
24906020
 
注:本文报道的变异用橙色标记。 F: 家系; OU:双眼 OD:右眼;OS:左眼;U: 单眼; “+”: 有该表型; “/”: 没有该表型;A: 无眼球;CH:小脑发育不全;ID:智力障碍;JC:关节屈曲挛缩;S:并指;SL:四肢短缩;MSL:轻微四肢短缩;NA: 未做相关检查;HGMD:人类基因突变数据库;ACMG:美国医学遗传和基因组学学会指南;UTR:非翻译区;DM:有害突变;D:有害的;T:耐受的;P:致病的;LP:可能致病的;VUS:意义不明确的;B:良性的。
Notes: The variants reported in this article were marked in orange. F: family; OU: both eyes; OD: right eye; OS: left eye; U: unilateral eye; "+": with this phenotype; "/": without this phenotype; A: anophthalmia; CH: cerebellar hypoplasia; ID: intellectual disability; JC: joint contracture; S: syndactylia; SL: shortened limbs; MSL: mildly shortened limbs; NA: not available; HGMD: The Human Gene Mutation Database; ACMG: American College of Medical Genetics and Genomics; UTR: untranslated region; DM: damaging mutations; D: damaging; T: tolerant; P: pathogenic; LP: likely pathogenic; VUS: variants uncertain significance; B: benign.

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1、 广州市科技计划项目(202201011073)。
This work was supported by the Science and Technology Projects in Guangzhou (202201011073), China.()
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