PDF(Pubmed)
Abstract：
UNASSIGNED: To determine the genetic causes of monogenic inherited diseases in a couple using clinical whole exome sequencing (WES) and advise on their reproductive choices.
UNASSIGNED: WES was applied to a couple seeking reproductive advice, the female with short stature and the male with congenital cataracts.
UNASSIGNED: (1) The woman exhibited a 13.8 Kb heterozygous deletion at chrX: 591590-605428 (hg19). This region corresponds to exons 2-6 of the short-stature homeobox-containing (SHOX) gene (NM000451). Associated diseases involving the SHOX gene range from severe Leri-Weill dyschondrosteosis to mild nonspecific short stature. Meanwhile, further validation using a quantitative reverse transcription polymerase chain reaction assay confirmed the heterozygous deletion of the SHOX gene in the proband, as well as other family members with similar clinical characteristics (the proband\'s mother, aunt, and cousin). Multiple pathogenic reports of this variant have been included in the HGMD database. Per the American College of Medical Genetics and Genomics (ACMG) classification criteria, this deletion is classified as pathogenic. (2) For the male patient, a heterozygous variant was detected in the CRYBB3 gene: NM004076: c.226G>A (p.Gly76R). Variants in the CRYBB3 gene can cause Cataract 22 (OMIM: 609741). At present, this variant locus is not included in databases such as the gnomAD, while both SIFT and PolyPhen2 deem this locus \'damaging\'. Moreover, further validation by Sanger sequencing confirmed that the variant was inherited from the male patient\'s mother, who also had cataracts. According to ACMG standards and guidelines, the c.226G>A (p.Gly76Arg) variant in the CRYBB3 gene is classified as having \'uncertain significance\'.
UNASSIGNED: WES identified pathogenic variants in both individuals, suggesting a 25% chance of a healthy child naturally. Third-generation assisted reproductive techniques are recommended to minimize the risk of affected offspring.
UNASSIGNED: WES was applied to a couple seeking reproductive advice, the female with short stature and the male with congenital cataracts.
UNASSIGNED: (1) The woman exhibited a 13.8 Kb heterozygous deletion at chrX: 591590-605428 (hg19). This region corresponds to exons 2-6 of the short-stature homeobox-containing (SHOX) gene (NM000451). Associated diseases involving the SHOX gene range from severe Leri-Weill dyschondrosteosis to mild nonspecific short stature. Meanwhile, further validation using a quantitative reverse transcription polymerase chain reaction assay confirmed the heterozygous deletion of the SHOX gene in the proband, as well as other family members with similar clinical characteristics (the proband\'s mother, aunt, and cousin). Multiple pathogenic reports of this variant have been included in the HGMD database. Per the American College of Medical Genetics and Genomics (ACMG) classification criteria, this deletion is classified as pathogenic. (2) For the male patient, a heterozygous variant was detected in the CRYBB3 gene: NM004076: c.226G>A (p.Gly76R). Variants in the CRYBB3 gene can cause Cataract 22 (OMIM: 609741). At present, this variant locus is not included in databases such as the gnomAD, while both SIFT and PolyPhen2 deem this locus \'damaging\'. Moreover, further validation by Sanger sequencing confirmed that the variant was inherited from the male patient\'s mother, who also had cataracts. According to ACMG standards and guidelines, the c.226G>A (p.Gly76Arg) variant in the CRYBB3 gene is classified as having \'uncertain significance\'.
UNASSIGNED: WES identified pathogenic variants in both individuals, suggesting a 25% chance of a healthy child naturally. Third-generation assisted reproductive techniques are recommended to minimize the risk of affected offspring.
摘要：
■使用临床全外显子组测序（WES）确定一对夫妇单基因遗传性疾病的遗传原因，并就他们的生殖选择提供建议。
■WES适用于一对寻求生殖建议的夫妇，女性身材矮小，男性患有先天性白内障。
■（1）该女子在chrX：591590-605428（hg19）处表现出13.8Kb的杂合缺失。该区域对应于含有矮小同源异型盒(SHOX)基因(NM000451)的外显子2-6。涉及SHOX基因的相关疾病范围从严重的Leri-Weill软骨发育不良到轻度非特异性身材矮小。同时,使用定量逆转录聚合酶链反应测定的进一步验证证实了先证者中SHOX基因的杂合缺失，以及其他具有相似临床特征的家庭成员(先证者的母亲，阿姨,和表弟）。HGMD数据库中已包含该变体的多种致病报告。根据美国医学遗传学和基因组学学院(ACMG)分类标准，这种缺失被归类为致病性。（2）对于男性患者，在CRYBB3基因中检测到杂合变体：NM004076：c.226G>A（p。Gly76R）。CRYBB3基因的变异可引起白内障22(OMIM:609741)。目前,该变异基因座不包括在数据库中，如gnomAD，而SIFT和PolyPhen2都认为这个地方“有害”。此外，通过Sanger测序的进一步验证证实该变异体遗传自男性患者的母亲，也有白内障。根据ACMG标准和指南，c.226G>A（p。CRYBB3基因中的Gly76Arg）变体被分类为具有“不确定的意义”。
■WES在两个个体中都发现了致病变异，表明健康孩子自然有25%的机会。建议使用第三代辅助生殖技术，以最大程度地减少受影响后代的风险。
■WES适用于一对寻求生殖建议的夫妇，女性身材矮小，男性患有先天性白内障。
■（1）该女子在chrX：591590-605428（hg19）处表现出13.8Kb的杂合缺失。该区域对应于含有矮小同源异型盒(SHOX)基因(NM000451)的外显子2-6。涉及SHOX基因的相关疾病范围从严重的Leri-Weill软骨发育不良到轻度非特异性身材矮小。同时,使用定量逆转录聚合酶链反应测定的进一步验证证实了先证者中SHOX基因的杂合缺失，以及其他具有相似临床特征的家庭成员(先证者的母亲，阿姨,和表弟）。HGMD数据库中已包含该变体的多种致病报告。根据美国医学遗传学和基因组学学院(ACMG)分类标准，这种缺失被归类为致病性。（2）对于男性患者，在CRYBB3基因中检测到杂合变体：NM004076：c.226G>A（p。Gly76R）。CRYBB3基因的变异可引起白内障22(OMIM:609741)。目前,该变异基因座不包括在数据库中，如gnomAD，而SIFT和PolyPhen2都认为这个地方“有害”。此外，通过Sanger测序的进一步验证证实该变异体遗传自男性患者的母亲，也有白内障。根据ACMG标准和指南，c.226G>A（p。CRYBB3基因中的Gly76Arg）变体被分类为具有“不确定的意义”。
■WES在两个个体中都发现了致病变异，表明健康孩子自然有25%的机会。建议使用第三代辅助生殖技术，以最大程度地减少受影响后代的风险。
