ORPHA: 1387;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q21.3 | Martsolf syndrome 2 | 619420 | Autosomal recessive | 3 | RAB3GAP1 | 602536 |
A number sign (#) is used with this entry because of evidence that Martsolf syndrome-2 (MARTS2) is caused by homozygous mutation in the gene encoding the catalytic subunit of RAB3 GTPase-activating protein (RAB3GAP1; 602536) on chromosome 2q21.
Mutation in the RAB3GAP1 gene can also cause Warburg Micro syndrome-1 (WARBM1; 600118), a clinically overlapping but more severe disorder.
Martsolf syndrome-2 (MARTS2) is an autosomal recessive disorder with the main features of congenital cataracts, mildly to severely impaired intellectual development, and facial dysmorphism. Other features include brain malformations, microcephaly, and hypogonadism-hypogenitalism (summary by Koparir et al., 2019).
Handley et al. (2013) reported 8.5- and 4.5-year-old sibs, born to consanguineous Egyptian parents (family K7), with short stature (-3.5 and -3.9 SD), microcephaly (-4.6 and -4.3 SD), and low weight (-1.4 and -3.1 SD), respectively. The older sib had bilateral congenital cataracts, moderate developmental delay, and hyperreflexia, and she was able to walk with assistance. She started to speak in sentences at age 7 years. A head CT showed brain atrophy. The younger sib had severe developmental delay, hyperreflexia, and bilateral congenital cataracts. He had a few words at age 3 years and was not yet walking. A brain MRI showed hypogenesis of the corpus callosum.
Koparir et al. (2019) reported a 14-year-old Turkish girl (family 1), born to consanguineous parents, with severely impaired intellectual development, spastic diplegia since 9 months of age, and cataracts that were operated on at 3 years of age. At age 12 years she had short stature (-2.5 SD), microcephaly (-3 SD), and low weight (-2.3 SD). Her facial features included deep-set eyes, large ears, and broad nasal tip. She also had mild camptodactyly of her fingers, overlapping toes, and hyperreflexia. Laboratory testing at age 14 years showed hypogonadotrophic hypogonadism. Brain MRI showed corpus callosum hypoplasia and an enlarged left ventricle.
The transmission pattern of MARTS2 in the families reported by Handley et al. (2013) and Koparir et al. (2019) was consistent with autosomal recessive inheritance.
In 2 sibs with Martsolf syndrome-2, born to consanguineous Egyptian parents (family K7), Handley et al. (2013) identified a homozygous frameshift mutation in the RAB3GAP1 gene (602536.0013). Studies in cDNA from one of the sibs showed increased expression of a region that contains an overlap between the full-length RAB3GAP1 transcript and an alternative RAB3GAP1 transcript. Handley et al. (2013) hypothesized that increased expression of the alternative transcript may have a compensatory effect on the loss of full-length protein, thus leading to Martsolf syndrome rather than the more severe Warburg Micro syndrome.
In a girl with Martsolf syndrome-2, who was born to consanguineous Turkish parents (family 1), Koparir et al. (2019) identified a homozygous splice site mutation in the RAB3GAP1 gene (602536.0014). The mutation was shown to result in reduced RAB3GAP1 expression.
Handley, M. T., Morris-Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S. M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., and 23 others. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in Warburg Micro syndrome and Martsolf syndrome. Hum. Mutat. 34: 686-696, 2013. [PubMed: 23420520] [Full Text: https://doi.org/10.1002/humu.22296]
Koparir, A., Karatas, O. F., Yilmaz, S. S., Suer, I., Ozer, B., Yuceturk, B., Ozen, M. Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes. Am. J. Med. Genet. 179A: 579-587, 2019. [PubMed: 30730599] [Full Text: https://doi.org/10.1002/ajmg.a.61065]