Abstract：
OBJECTIVE: Warburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.
METHODS: We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.
RESULTS: We reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.
CONCLUSIONS: WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.
METHODS: We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.
RESULTS: We reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.
CONCLUSIONS: WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.
摘要：
目的：WarburgMicro综合征（WARBM）是一种罕见的常染色体隐性遗传病，神经学，和内分泌异常。WARBM是由RAB3GAP1、RAB3GAP2、RAB18和TBC1D20突变引起的表型和遗传异质性综合征。在这里，我们介绍了一个具有WARBM表型的近亲突尼斯家族的临床和遗传特征，该家族表现出两种致病变异，其中之一是在RAB3GAP1上。
方法：我们将全外显子组测序（WES）应用于两名表现出WARBM相容性表型的年轻男性。
结果：我们揭示了RAB3GAP1的新变化（NM_012233.3：c.297del，p.Gln99fs）和ABCD1的另一种变化（NM_000033：c.896A>G，p.His299Arg).这些突变中的每一个，在计算机预测中得出结论为致病变异，影响一个关键的蛋白质区域。两名受影响的男性均表现出与WARBM兼容的表型，患有严重的智力残疾，严重的发育迟缓，产后生长延迟，产后小头畸形,先天性双侧白内障,一般低张力,和一个没有Spenium的薄call体。然而,家族内临床异质性存在，因为只有最大的孩子有大耳朵，小眼症,足部畸形,和生殖器异常，只有最小的孩子有微角膜。尽管在ABCD1中发现了突变，但我们的患者没有任何通常由ABCD1突变引起的肾上腺脑白质营养不良症的X连锁症状，这激发了我们对临床监测的兴趣。
结论：对具有WARBM的近亲突尼斯家族的WES分析揭示了RAB3GAP1的新变异（NM_012233.3：c.297del，p.Gln99fs）最有可能致病，使我们能够确认WARBM的诊断。
方法：我们将全外显子组测序（WES）应用于两名表现出WARBM相容性表型的年轻男性。
结果：我们揭示了RAB3GAP1的新变化（NM_012233.3：c.297del，p.Gln99fs）和ABCD1的另一种变化（NM_000033：c.896A>G，p.His299Arg).这些突变中的每一个，在计算机预测中得出结论为致病变异，影响一个关键的蛋白质区域。两名受影响的男性均表现出与WARBM兼容的表型，患有严重的智力残疾，严重的发育迟缓，产后生长延迟，产后小头畸形,先天性双侧白内障,一般低张力,和一个没有Spenium的薄call体。然而,家族内临床异质性存在，因为只有最大的孩子有大耳朵，小眼症,足部畸形,和生殖器异常，只有最小的孩子有微角膜。尽管在ABCD1中发现了突变，但我们的患者没有任何通常由ABCD1突变引起的肾上腺脑白质营养不良症的X连锁症状，这激发了我们对临床监测的兴趣。
结论：对具有WARBM的近亲突尼斯家族的WES分析揭示了RAB3GAP1的新变异（NM_012233.3：c.297del，p.Gln99fs）最有可能致病，使我们能够确认WARBM的诊断。
