van Rahden Vanessa A, Rau Isabella, Fuchs Sigrid, Kosyna Friederike K, de Almeida Hiram Larangeira, Fryssira Helen, Isidor Bertrand, Jauch Anna, Joubert Madeleine, Lachmeijer Augusta M A, Zweier Christiane, Moog Ute, Kutsche Kerstin
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
Orphanet J Rare Dis. 2014 Apr 15;9:53. doi: 10.1186/1750-1172-9-53.
Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.
We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.
Two terminal Xp deletions of ≥ 11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥ 3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.
Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.
Xp22.2节段性单体或杂合性HCCS突变与小眼症合并线性皮肤缺损（MLS）或MIDAS（小眼症、皮肤发育不全和硬化性角膜）综合征相关，这是一种具有男性致死性的X连锁疾病。HCCS编码参与线粒体氧化磷酸化（OXPHOS）和程序性细胞死亡的全细胞色素c型合成酶。
我们通过细胞遗传学分析、荧光原位杂交、测序和定量实时PCR，对6例具有MLS表型的新的女性患者中包含HCCS的X染色体异常或该基因的基因内突变进行了特征分析。确定了X染色体失活（XCI）模式，并回顾了患者的临床资料。
报告了两个≥11.2 Mb的末端Xp缺失、两个亚微观拷贝数缺失，一个约850 kb，另一个≥3 Mb，均覆盖HCCS，HCCS中有1个无义突变和1个镶嵌2 bp缺失。所有女性的XCI模式均完全（>98:2）或轻度偏斜（82:18）。最一致的临床特征是所有患者均有小眼症/无眼症和硬化性角膜/角膜混浊，4/6患者有先天性线性皮肤缺损。其他表现包括各种眼部异常、心脏缺陷、脑成像异常、小头畸形、出生后生长迟缓和面型畸形。然而，在一名患者的三名女性携带者亲属中未观察到明显的临床体征。
我们的研究结果显示了广泛的表型谱，从携带HCCS突变的无症状女性到新生儿致死性MLS形式的患者。体细胞镶嵌现象以及胚胎细胞在HCCS缺陷时应对OXPHOS缺陷和/或增强细胞死亡的不同能力可能是表型高度变异的基础。
