A null mutation in a patient can facilitate phenotype assignment and uncovers the function of that specific gene. We present five sibs of a consanguineous Pakistani family afflicted with a new syndrome with an unusual combination of skeletal anomalies including cranial asymmetry, fused sagittal sutures deviating from the medial axis, mandibular prognathia, maxillary hypoplasia, misaligned and crowded teeth, delayed bone age, multiple dislocations, hypoplastic and malpositioned patellae, humeral intracondylar fissures, scapular dyskinesis, long limbs, lumbar lordosis, protruding chest, prominent clavicles, short 5th digital rays, and ventral transverse digital creases plus features of cutis laxa. We mapped the disease gene locus to a 3.62-Mb region at 17q25.3 and identified a homozygous deletion of maximal 7.3 kb deduced to totally inactivate MYADML2 and downstream gene PYCR1, biallelic variants in which cause autosomal recessive cutis laxa (ARCL). All five affected sibs had the most common features of ARCL but not many of the less common ones. We attributed the anomalies not typical for ARCL to MYADML2 deficit, because no other genetic defect possibly a candidate to underlie the skeletal phenotype was found. MYADML2 is a gene of unknown function, has not been studied, and has not been associated with disease. Our findings present a possible phenotype for MYADML2 deficit that includes impaired bone patterning and maturation, definitely show that the gene is not essential for survival, and provide a start point for future studies on the function of MYADML2 protein. Detection of new patients is needed to confirm and delineate MYADML2-deficiency phenotype.

患者中的无效突变可以促进表型分配并揭示该特定基因的功能。我们介绍了一个患有新综合征的近亲巴基斯坦家庭的五个同胞，这些骨骼异常包括颅骨不对称，融合矢状缝线偏离中轴，下颌前突，上颌发育不全，牙齿不齐和拥挤，牙齿延迟，骨龄延迟，多发性骨异常脱位，hypo骨发育不良和错位，肱骨con内裂，肩cap运动障碍，长肢，腰椎前凸，胸部突出，锁骨突出，第5指短射线和腹侧横指皱纹以及角质疏松特征。我们将疾病基因位点定位到17q25.3处的3.62-Mb区域，并确定了最大7.3 kb的纯合缺失，推断其完全失活MYADML2和下游基因PYCR1是双等位基因变异体，在这些变异体中导致常染色体隐性角质松弛（ARCL）。所有五个受影响的同胞都具有ARCL的最常见特征，但不太常见的同胞并不很多。我们将非典型ARCL异常归因于MYADML2缺陷，因为没有发现可能是骨骼表型基础的其他遗传缺陷。MYADML2是功能未知的基因，尚未研究，也未与疾病相关。我们的发现提出了MYADML2缺陷的可能表型，包括受损的骨形成和成熟，明确表明该基因对于存活不是必需的，并为MYADML2蛋白功能的未来研究提供了起点。需要检测新患者以确认和描绘MYADML2缺陷表型。