Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
Reconciling newborn screening and a novel splice variant in BTD associated with partial biotinidase deficiency: a BabySeq Project case report
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DOI：
10.1101/mcs.a002873
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发表时间：
2018-08-01
影响因子：
1.8
通讯作者：
Rehm, Heidi L.
中科院分区：
文献类型：
--
作者：
Murry, Jaclyn B.;Machini, Kalotina;Rehm, Heidi L.
在这里，我们报告了一个来自BabySeq项目的健康婴儿队列的新生女婴，她被鉴定为复合杂合BTD基因变异。鉴定出的两种变异包括一种已确定的致病变异（c.1612C >t, p.Arg538Cys），该变异导致纯合性严重生物素酶缺乏症（BID）。此外，在内含子1的不变剪接供体区域发现了一种新的剪接变体（c.44+1G> a, p.?），可能预示着功能丧失。预计这种新变异会影响外显子1的剪接；然而，考虑到在GTEx数据库中大多数组织中外显子1中没有任何报道的致病变异，以及外显子1缺失的选择性剪接，我们分配了一个不确定意义的初始分类。对国家规定的新生儿筛查（NBS）结果的后续医疗记录审查显示，最初的生物素酶活性水平超出范围。从一个重复的国家统计局样本的水平勉强通过截止到正常范围。为了确定婴儿是否缺乏生物素酶，随后进行了诊断性酶活性测试，确认部分BID，并导致该患者的管理改变。这导致了基于这些结果的新剪接变体的重新分类。总之，将遗传和NBS结果结合在一起，促进了临床随访，证实了部分BTD，并为该新剪接位点的重新分类提供了信息，强调了结合迭代遗传和表型评估的重要性。
Here, we report a newborn female infant from the well-baby cohort of the BabySeq Project who was identified with compound heterozygous BTD gene variants. The two identified variants included a well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BID) in homozygosity. In addition, a novel splice variant (c.44+1G>A, p.?) was identified in the invariant splice donor region of intron 1, potentially predictive of loss of function. The novel variant was predicted to impact splicing of exon 1; however, given the absence of any reported pathogenic variants in exon 1 and the presence of alternative splicing with exon 1 absent in most tissues in the GTEx database, we assigned an initial classification of uncertain significance. Follow-up medical record review of state-mandated newborn screen (NBS) results revealed an initial out-of-range biotinidase activity level. Levels from a repeat NBS sample barely passed cut-off into the normal range. To determine whether the infant was biotinidase-deficient, subsequent diagnostic enzyme activity testing was performed, confirming partial BID, and resulted in a change of management for this patient. This led to reclassification of the novel splice variant based on these results. In conclusion, combining the genetic and NBS results together prompted clinical follow-up that confirmed partial BTD and informed this novel splice site's reclassification, emphasizing the importance of combining iterative genetic and phenotypic evaluations.